Ip and ip analogs dosage regimens for the treatment of ectopic calcifications

ABSTRACT

The present disclosure related to compositions, methods, dosages, dosage regimens, articles of manufacture and kits for the treatment and/or prevention ectopic calcifications, and in particular cutaneous calcifications such as calciphylaxis calcifications comprising inositol phosphate, inositol phosphate analogs, inositol phosphate derivatives, or combinations thereof. In a particular aspect the disclosure provides a dosage regimen to treat calciphylaxis comprising the administration of 6 mg/kg to 9 mg/kg daily doses of myo-inositol hexaphosphate, three times a week, for at least 1 to 8 months.

BACKGROUND Field

The present disclosure is related to compositions and methods to treatand/or prevent ectopic calcifications comprising the administration ofinositol phosphates, their analogs and derivatives.

Background

Cutaneous and subcutaneous calcifications (in general referred to asectopic calcifications) arise as complications in numerous diseases.Ectopic calcifications can be classified into dystrophic, metastatic,idiopathic, or iatrogenic calcifications, or into calciphylaxis.Calciphylaxis corresponds to the calcification of small sized bloodvessels and of the sub-cutaneous adipose tissue. Most of the timecalciphylaxis is secondary to chronic renal failure, and it is oftenassociated with abnormalities of calcium and phosphate metabolism.However, it remains a separate entity given its specific pathophysiologyand its particular evolutionary modalities.

Beyond the abnormal nature of their presence, these calcifications cancause complications in terms of functional capability (e.g., limitationof range of motion and joint function), pain (e.g., very painful natureof some calcifications, particularly in calciphylaxis) or on the trophiclevel (e.g., ischemia and necrosis of the cutaneous and subcutaneoustissues) that can lead to additional infectious complications.

Although a number of treatments have been tried and reported (e.g.,bisphosphonates, calcium channel blockers, probenecid) for thesecutaneous and subcutaneous calcifications, to date there is no existingcurative treatment for which efficacy has been demonstrated with asufficient level of proof.

Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), is asevere form of vascular calcification that affects approximately 1% to4% of patients with end-stage renal disease, almost exclusively thosewho are on hemodialysis. See, e.g., Angelis et al. (1997) Surgery122:1083-1089; Budisavljevic et al. (1996) J. Am. Soc. Nephrol.7:978-982; Levin et al. (1993) Am. J. Nephrol. 13:448-453. One-yearmortality for calciphylaxis has been reported to be between 45% and 80%,with ulcerated lesions being associated with higher mortality thannon-ulcerated lesions (Nigwekar et al. (2015) Am. J. Kidney Dis.66:133-146; Hafner et al. (1995) J. Am. Acad. Dermatol. 33:954-962; Fine& Zacharias (2002) Kidney International 61:2210-2217; Weenig et al.(2007) J. Am. Acad. Dermatol. 56:569-579).

In calciphylaxis, progressive, painful, necrotic skin ulcers result fromcalcification of small peripheral vessels. Mochel at al. (2013) Am. J.Dermatopathol. 35:582-586. Current treatment paradigm is palliative andbased on anecdotal clinical data. Options include, e.g., intravenoussodium thiosulfate, bisphosphonates, and switching from calcium-based tonon-calcium-based phosphate binders, but there are no approved therapiesfor calciphylaxis. The focus of treatment in calciphylaxis is oftensymptomatic, comprising wound care and pain management, rather thantreating the underlying cause. Nigwekar et al. (2015) Am. J. Kidney Dis.66:133-146.

Accordingly, there is a need for new therapeutic approaches to treatcalciphylaxis, and ectopic calcifications in general.

BRIEF SUMMARY

The present disclosure provides methods to treat and/or prevent ectopiccalcification (e.g., calciphylaxis calcifications) and/or theconsequences thereof in a subject in need thereof comprisingadministering at least one dose of an inositol phosphate of thedisclosure (e.g., inositol hexaphosphate or an analog or derivativethereof), or a combination thereof, in a dosage of about 6 mg to 9 mgper kg per day to the subject, wherein the administration of the dosageeffectively treats or prevents ectopic calcification and/or theconsequences thereof in the subject.

In some aspects, the inositol phosphate of the disclosure (e.g.,inositol hexaphosphate or an analog or derivative thereof) comprises acompound of formula I, a pharmaceutically acceptable salt thereof, or acombination thereof:

wherein

-   (i) R₁, R₃, R₅, R₇, and R₉ independently represent OH, a compound of    formula II, or a compound of formula III, or a compound for formula    IV:

-   (ii) R₂, R₄, R₆, R₈, R₁₀, R₁₂ and R₁₃ represent H;-   (iii) at least one of R₁, R₃, R₅, R₇, R₉ and R₁₁ represents a    compound of formula II, formula III or formula IV, and-   (iv) zero, one, or two of R₁, R₃, R₅, R₇, R₉ and R₁₁ represent a    heterologous moiety.

In some aspects, the heterologous moiety confers an advantageousproperty to the inositol phosphate of the disclosure, e.g., a half-lifeextending moiety that would confer extended plasma half-life, ametabolism-modulating moiety, or a solubility-enhancing heterologousmoiety.

In some aspects, the heterologous moiety comprises, e.g., a polyethyleneglycol, a polyglycerol, or a combination thereof. In some aspects, theinositol phosphate of the disclosure is myo-inositol hexaphosphate. Insome aspects, the concentration of inositol phosphate of the disclosure(e.g., inositol hexaphosphate or an analog or derivative thereof)thereof in each dose is between about 10,000 μg/mL 100,000 μg/mL. Insome aspects, the concentration of inositol phosphate of the disclosure(e.g., inositol hexaphosphate or an analog or derivative thereof) ineach dose is between about 12.5 mM and about 135 mM.

In some aspects, the dosage is administered as a single daily dose. Insome aspects, the dosage is administered as multiple daily doses. Insome aspects, the dosage is administered at least once a week. In someaspects, the dosage is administered 2, 3, 4, 5, 6 or 7 times per week.In some aspects, the dosage is administered for at least one week. Insome aspects, the dosage is administered for about 2, 3, 4, 5, 6, 7, 8,9, 10, 11 or 12 weeks. In some aspects, the dosage is administered forat least 12 weeks. In some additional aspects, the dosage isadministered for about 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24weeks. In some further aspects, the dosage is administered for at least24 weeks. In some ulterior aspects, the dosage is administered for about25, 26, 27, 28, 29, 30, 31 or 32 weeks. In some other aspects, thedosage is administered for at least 32 weeks.

In some aspects, the administration of the dosage to the subjectinhibits the formation and/or growth of hydroxyapatite crystals. In someaspects, the ectopic calcification arises from, or is related to, thepathological crystallization of calcium. In some aspects, the ectopiccalcification is calciphylaxis calcification, metastatic calcification,dystrophic calcification, iatrogenic calcification, idiopathiccalcification, or subcutaneous ectopic ossification. In some aspects,the consequence of the ectopic calcification is a functionalcomplication, pain, a trophic complication, an infection, or acombination thereof. In some aspects, the function complication is alimitation of range of motion and/or joint function.

In some aspects, the trophic complication is ischemia and/or a lesion.In some aspects, the lesion is necrosis of the cutaneous and/orsubcutaneous tissues. In some aspects, administration of the dosage tothe subject causes a reduction in lesions as determined by theBates-Jensen Wound Assessment tool. Bates-Jensen (1992) Decubitus5(6):20-28. In some aspects, the reduction in lesions comprises areduction in the severity of the lesions, a reduction in the size of thelesions, and reduction in the duration of the lesions, or a combinationthereof. In some aspects, administration of the dosage to the subjectcauses an improvement in lesion healing.

In some aspects, administration of the dosage to the subject causes areduction in pain. In some aspects, administration of the dosage to thesubject causes an improvement on global wound quality of life (QoL) asdetermined by using a validated wound-associated QoL questionnaire.Augustin et al. (2017) Int'l. Wound J. 12:1299-1304. In some aspects,the subject has end-stage renal disease. In some aspects, the subject ison hemodialysis. In some aspects, subject is human.

In some aspects, the administration is parenteral. In some aspects, theparenteral administration is by bolus injection or by intravenousinfusion. In some aspects, the administration is topical.

The present disclosure also provides a method to treat or preventcalciphylaxis calcification and/or the consequences thereof in a subjectin need thereof comprising administering an intravenous dose of aninositol phosphate of the present disclosure, e.g., myo-inositolhexaphosphate, or an analog or derivative thereof, in a dosage of about6 mg to 9 mg per kg per day to the subject, administered 3 times a weekfor 12 or 24 weeks, wherein the administration of the dosage effectivelytreats or prevents calciphylaxis calcification and/or the consequencesthereof in the subject. In some aspects, a dosage of inositol phosphateof about 7 mg per kg per day is administered 3 times a week for 12 or 24weeks.

The presents disclosure also provides an intravenous dose of an inositolphosphate of the present disclosure, e.g., myo-inositol hexaphosphate,or an analog or derivative thereof, in a dosage of about 6 mg to 9 mgper kg per day to the subject, administered 3 times a week for 12 or 24weeks as taken by a patient in a therapeutically effective amountsufficient to treat or prevent calciphylaxis calcification and/or theconsequences thereof in a subject. In some aspects, a dosage of inositolphosphate of about 7 mg per kg per day is administered 3 times a weekfor 12 or 24 weeks.

The present disclosure also provides a kit or article of manufacturecomprising at least one container comprising a parenteral or topicaldose of an inositol phosphate of the present disclosure, e.g., inositolhexaphosphate or an analog or derivative thereof, and instructions foradministration according to any method disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

FIG. 1 is a simplified schematic representation of the physiochemicalmechanism of action of SNF472, a formulation of myo-inositolhexaphosphate. SNF472 inhibits cardiovascular calcification, e.g., byblocking new calcium crystal formation and the growth of existingcrystals. SNF472 is an intravenous formulation of myo-inositolhexaphosphate, which selectively inhibits the formation and growth ofhydroxyapatite crystals, the final common pathway in the pathophysiologyof vascular calcification. Phase 1 studies in healthy volunteers andhemodialysis patients showed the tolerability and inhibition ofhydroxyapatite crystal formation with SNF472. The phase 2 studypresented in the Examples section of the present disclosure evaluatedwound healing, pain, and quality of life with SNF472 treatment inend-stage renal disease patients on hemodialysis with calciphylaxis.

FIG. 2A shows that in the intention-to-treat population with multipleimputation (n=14), SNF472 treatment resulted in a statisticallysignificant improvement in mean total Bates-Jensen Wound Assessment Tool(BWAT) score for the primary lesion from baseline to week 12.

FIG. 2B shows that, using only observed data, SNF472 treatment resultedin progressive improvement in mean total BWAT scores at each visit, withstatistically significant improvements at weeks 10 and 12. *p<0.05 forthe change from baseline.

FIG. 3. SNF472 treatment for 12 weeks was associated with improvementfrom baseline for most of the Bates-Jensen Wound Assessment Toolcomponent scores for the primary lesion. *p<0.05 for the change frombaseline.

FIG. 4A shows that, in the intention-to-treat population with multipleimputation (n=14), SNF472 treatment resulted in a statisticallysignificant improvement in pain visual analog scale (VAS) score for theprimary lesion from baseline to week 12.

FIG. 4B shows that, using only observed data, SNF472 treatment resultedin statistically significant improvement of pain VAS scores for theprimary lesion from baseline to weeks 6, 8, and 12. *p<0.05 for thechange from baseline.

FIG. 5 shows that in the intention-to-treat population with multipleimputation (n=14), SNF472 treatment resulted in subject-reportedimprovements in quality of life (QoL) scores from baseline to week 12.

FIG. 6 shows that a qualitative unblinded review of wounds reportedimprovement from baseline for 8 of 11 (72.7%) subjects at week 12 ofSNF472 treatment. One of the 2 patients that worsened did not havedetectable SNF472 plasma levels. The other patient was equal tobaseline.

FIG. 7 shows representative images for qualitative wound assessment atbaseline and at week 12 for the primary lesion. *Plasma SNF472concentration was below the limit of quantification in Subject 6 who hadlesion worsening; plasma SNF472 concentration was in the expected rangein all other subjects.

FIG. 8 shows representative inositol phosphate analogs in which two outof six X are OPSO₂ ²⁻ and the remaining X are OSO₃ Four specific formsof 4,6-di-(O-thiophosphate)-inositol-1,2,3,5-tetra-O-sulfate are shown.

FIG. 9 shows inositol phosphate analogs and inositol phosphatederivatives that can be used to practice the methods of the presentdisclosure. The molecules shown aremyo-inositol-pentakisphosphate-2-PEG400, myo-inositol hexakissulfate(myo-inositol hexasulfate), and scyllo-myo-inositol hexakissulfate(scyllo-inositol hexasulfate).

FIG. 10 shows inositol phosphate analogs and inositol phosphatederivatives that can be used to practice the methods of the presentdisclosure. X represent independently phosphor and/or sulfur containinggroups, e.g., phosphate, sulfate, or thiophosphate. R¹ represents aheterologous moiety, e.g., PEG or PG.

FIG. 11 shows exemplary inositol phosphate analogs and inositolphosphate derivatives that can be used to practice the methods of thepresent disclosure. R¹ represents a heterologous moiety, e.g., PEG orPG. n can be between 2 and 200.

FIG. 12 shows exemplary inositol phosphate analogs and inositolphosphate derivatives that can be used to practice the methods of thepresent disclosure. n can be between 2 and 200.

FIG. 13 shows exemplary inositol phosphate analogs and inositolphosphate derivatives that can be used to practice the methods of thepresent disclosure. n can be between 2 and 200.

DETAILED DESCRIPTION

The present disclosure provides compositions, dosages, dosage regimens,methods, pharmaceutical compositions and formulations, methods of use,articles of manufacture, and kits for the treatment of ectopiccalcifications in general, and calciphylaxis calcifications inparticular. The disclosure provides method to treat and/or preventectopic calcifications and/or the consequences thereof in a subject inneed thereof comprising administering at least one dose of an inositolphosphate of the present disclosure (e.g., an inositol phosphate, aninositol phosphate analog, an inositol phosphate derivative, or acombination thereof), in a dosage disclosed herein, e.g., of about 6 mgto 9 mg per kg per day, to the subject, wherein the administration ofthe dosage effectively treats and/or prevents ectopic calcificationand/or the consequences thereof in the subject.

The disclosure also provides dosage forms comprising an amount ofinositol phosphate of the present disclosure (e.g., an inositolphosphate, an inositol phosphate analog, an inositol phosphatederivative, or a combination thereof) sufficient to administer a dosedisclosed herein, e.g., a dose of about 6 mg to 9 mg per kg, to thesubject. Also provided are pharmaceutical compositions and formulationscomprising an amount of an inositol phosphate of the present disclosure(e.g., an inositol phosphate, an inositol phosphate analog, an inositolphosphate derivative, or a combination thereof) sufficient toadminister, e.g., a dose of about 6 mg to 9 mg per kg to the subject.

The disclosure also provides articles of manufacture and kits comprisingat least one vessel or container containing an amount of an inositolphosphate of the present disclosure (e.g., an inositol phosphate, aninositol phosphate analog, an inositol phosphate derivative, or acombination thereof) sufficient to administer, e.g., a dose of about 6mg to 9 mg per kg to the subject, or multiple doses, as well asinstructions to administer such doses according to the methods disclosedherein.

In order that the present disclosure can be more readily understood,certain terms are first defined below. As used in this application,except as otherwise expressly provided herein, each of the followingterms shall have the meaning set forth below. Additional definitions areset forth throughout the application.

I. Definitions

The disclosure includes aspects in which exactly one member of the groupis present in, employed in, or otherwise relevant to a given product orprocess. The disclosure includes aspects in which more than one, or allof the group members are present in, employed in, or otherwise relevantto a given product or process.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure is related. For example, the ConciseDictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed.,2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed.,1999, Academic Press; and the Oxford Dictionary Of Biochemistry AndMolecular Biology, Revised, 2000, Oxford University Press, provide oneof skill with a general dictionary of many of the terms used in thisdisclosure.

Units, prefixes, and symbols are denoted in their Systeme Internationalde Unites (SI) accepted form. Numeric ranges are inclusive of thenumbers defining the range. Where a range of values is recited, it is tobe understood that each intervening integer value, and each fractionthereof, between the recited upper and lower limits of that range isalso specifically disclosed, along with each subrange between suchvalues. The upper and lower limits of any range can independently beincluded in or excluded from the range, and each range where either,neither or both limits are included is also encompassed within theinvention.

Where a value is explicitly recited, it is to be understood that valueswhich are about the same quantity or amount as the recited value arealso within the scope of the invention. Where a combination isdisclosed, each subcombination of the elements of that combination isalso specifically disclosed and is within the scope of the invention.Conversely, where different elements or groups of elements areindividually disclosed, combinations thereof are also disclosed. Whereany element of an invention is disclosed as having a plurality ofalternatives, examples of that invention in which each alternative isexcluded singly or in any combination with the other alternatives arealso hereby disclosed; more than one element of an invention can havesuch exclusions, and all combinations of elements having such exclusionsare hereby disclosed.

About: The term “about” as used herein to a value or composition that iswithin an acceptable error range for the particular value or compositionas determined by one of ordinary skill in the art, which will depend inpart on how the value or composition is measured or determined, i.e.,the limitations of the measurement system. For example, “about” can meanwithin 1 or more than 1 standard deviation per the practice in the art.Alternatively, “about” can mean a range of up to 20%. Furthermore,particularly with respect to biological systems or processes, the termscan mean up to an order of magnitude or up to 5-fold of a value.

When particular values or compositions are provided in the applicationand claims, unless otherwise stated, the meaning of “about” should beassumed to be within an acceptable error range for that particular valueor composition. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. Thus, “about 10-20”means “about 10 to about 20.” In general, the term “about” can modify anumerical value above and below the stated value by a variance of, e.g.,10 percent, up or down (higher or lower).

And/or: “And/or” where used herein is to be taken as specific disclosureof each of the two specified features or components with or without theother. Thus, the term “and/or” as used in a phrase such as “A and/or B”herein is intended to include “A and B,” “A or B,” “A” (alone), and “B”(alone). Likewise, the term “and/or” as used in a phrase such as “A, B,and/or C” is intended to encompass each of the following aspects: A, B,and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A(alone); B (alone); and C (alone).

Approximately: As used herein, the term “approximately,” as applied toone or more values of interest, refers to a value that is similar to astated reference value. In certain aspects, the term “approximately”refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, or less in either direction (greater than or less than)of the stated reference value unless otherwise stated or otherwiseevident from the context (except where such number would exceed 100% ofa possible value).

Comprising: It is understood that wherever aspects are described hereinwith the language “comprising,” otherwise analogous aspects described interms of “consisting of” and/or “consisting essentially of” are alsoprovided.

Compound: As used herein, the term “compound,” is meant to include allisomers and isotopes of the structure depicted. As used herein, the term“isomer” means any geometric isomer, tautomer, zwitterion, stereoisomer,enantiomer, or diastereomer of a compound. Compounds can include one ormore chiral centers and/or double bonds and can thus exist asstereoisomers, such as double-bond isomers (i.e., geometric E/Z isomers)or diastereomers (e.g., enantiomers (i.e., (+) or (−)) or cis/transisomers). The present invention encompasses any and all isomers of thecompounds described herein, including stereomerically pure forms (e.g.,geometrically pure, enantiomerically pure, or diastereomerically pure)and enantiomeric and stereoisomeric mixtures, e.g., racemates.Enantiomeric and stereomeric mixtures of compounds and means ofresolving them into their component enantiomers or stereoisomers arewell-known. A compound, salt, or complex of the present disclosure canbe prepared in combination with solvent or water molecules to formsolvates and hydrates by routine methods. In some aspects, the termcompound is used to refer to an inositol phosphate of the presentdisclosure.

Consequence of ectopic calcification: The terms “consequence of ectopiccalcification” or the term “consequences thereof” used in reference toectopic calcifications refer to any complications related to thepresence of an ectopic calcification, e.g., a calciphylaxiscalcification. This type of complication can be for example a functionalcomplication (e.g., a limitation of range of motion and joint function),pain, a trophic complication (e.g., ischemia or necrosis of thecutaneous and/or subcutaneous tissues), an infection, or a combinationthereof.

Ectopic calcification: The term “ectopic calcification” as used hereinrefers to all pathological deposits of calcium salts or any bone growthin the tissues, in particular in a soft tissue. Examples of diseasesand/or conditions related to the pathological crystallization of calciuminclude, but are not limited to, aortic stenosis, atherosclerosis,calcinosis cutis, calciphylaxis (CUA), cardiovascular mortality,chondrocalcinosis, coronary artery disease, critical limb ischemia,failure of renal transplant grafts and peripheral arterial disease,general arterial calcification of infancy (GACI), kidney stones,myocardial infarction, nephrocalcinosis, osteoporosis, primaryhyperoxaluria (PH), progression of chronic kidney disease, pseudogout,pseudoxanthoma elasticum (PXE), valvular calcification, vascularcalcification, and vascular stiffening. In some aspects, the ectopiccalcification is, e.g., a metastatic calcification, a dystrophiccalcification, an iatrogenic calcification, an idiopathic calcification,a calcification associated with calciphylaxis, a subcutaneous ectopicossification. In one specific aspect, the ectopic calcification is acalciphylaxis calcification.

Effective Amount: As used herein, the term “effective amount” of atherapeutic agent, in reference to (i) an inositol phosphate of thepresent disclosure (e.g., an inositol phosphate, an inositol phosphateanalog, an inositol phosphate derivative, or a combination thereof),(ii) any dosage form, pharmaceutical composition, or formulationdisclosed herein comprising an inositol phosphate of the presentdisclosure, or (iii) a combination of an inositol phosphate of thepresent disclosure with one or more additional therapeutic agents), isthat amount sufficient to effect beneficial or desired results. In someaspects, the beneficial or desired results are, for example, clinicalresults, and, as such, an “effective amount” depends upon the context inwhich it is being applied. For example, in the context of administeringa therapeutic agent that treats ectopic calcification, an effectiveamount of a therapeutic agent is, for example, an amount sufficient toreduce or decrease the size of a calcification and/or to inhibitformation and/or growth of calcifications, as compared to thecalcifications observed in the subject prior to the administration ofthe therapeutic agent, or in a population of control subjects withoutadministration of the therapeutic agent. The term “effective amount” canbe used interchangeably with “effective dose,” “therapeuticallyeffective amount,” or “therapeutically effective dose.”

Prophylaxis: As used herein, the term “prophylaxis” refers to a measuretaken to maintain health and prevent or delay the onset of a disease orcondition or to mitigate its extent and/or severity of the symptoms.Thus, a prophylactic use of a therapeutic agent disclosed herein, forexample, (i) an inositol phosphate of the present disclosure (e.g., aninositol phosphate, an inositol phosphate analog, an inositol phosphatederivative, or (ii) a combination thereof), or any dosage form,pharmaceutical composition, or (iv) formulation disclosed hereincomprising an inositol phosphate of the present disclosure, or a (iv)combination of an inositol phosphate of the present disclosure with oneor more additional therapeutic agents, corresponds to that amountsufficient to effect beneficial or desired results. For example,clinical results that would prevent the development of ectopiccalcification or delay the appearance of calcifications in a subject.

Ranges: As described herein, any concentration range, percentage range,ratio range or integer range is to be understood to include the value ofany integer within the recited range and, when appropriate, fractionsthereof (such as one tenth and one hundredth of an integer), unlessotherwise indicated.

SNF472: As used herein, the term “SNF472” refers to an intravenousmyo-inositol hexaphosphate formulation. SNF472 is manufactured bydissolving myo-inositol hexaphosphate in saline solution, followed by pHadjustment and aseptic filtration. SNF472 is prepared at three differentstrengths: (a) (i) 20 mg/mL and (ii) 90 mg/mL in 5 mL single-use vials,formulated in saline solution, pH 5.8 to 6.2 and (b) 30 mg/L in 10 mLsingle-use vials, formulated in saline solution, pH 5.6 to 6.4.

Soft tissue: The term “soft tissue” refers to a tissue other than bonetissue, which connects, supports, or surrounds other structures andorgans of the body.

Subject: By “subject” or “individual” or “animal” or “patient” or“mammal,” is meant any subject, particularly a mammalian subject, forwhom diagnosis, prognosis, or therapy is desired. Mammalian subjectsinclude, but are not limited to, humans, domestic animals, farm animals,zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs,rabbits, rats, mice, horses, cattle, cows; primates such as apes,monkeys, orangutans, and chimpanzees; canids such as dogs and wolves;felids such as cats, lions, and tigers; equids such as horses, donkeys,and zebras; bears, food animals such as cows, pigs, and sheep; ungulatessuch as deer and giraffes; rodents such as mice, rats, hamsters andguinea pigs; and so on. In certain aspects, the mammal is a humansubject. In other aspects, a subject is a human patient. In a particularaspect, a subject is a human patient with a pathological calcificationor at risk of having pathological calcifications. In some embodiments,the subject is a human patient with a pathological calcification, forexample an ectopic calcification such as a calciphylaxis calcificationin need of treatment.

Substantially: As used herein, the term “substantially” refers to thequalitative condition of exhibiting total or near-total extent or degreeof a characteristic or property of interest. One of ordinary skill inthe biological arts will understand that biological and chemicalphenomena rarely, if ever, go to completion and/or proceed tocompleteness or achieve or avoid an absolute result. The term“substantially” is therefore used herein to capture the potential lackof completeness inherent in many biological and chemical phenomena.

Therapeutic agent: As used herein, the term “therapeutic agent” is usedin a broad sense to include a composition comprising an inositolphosphate of the present disclosure that can provide a significanttherapeutic benefit to a subject in need thereof, in particular, asubject suffering from or at risk of developing ectopic calcifications.Thus, a therapeutic agent according to the present disclosure can be,for example, (i) any inositol phosphate of the present disclosure (e.g.,an inositol phosphate, an inositol phosphate analog, an inositolphosphate derivative, or a combination thereof), or (ii) any dosageform, pharmaceutical composition, or formulation disclose hereincomprising an inositol phosphate of the present disclosure, or (iii) acombination of an inositol phosphate of the present disclosure with oneor more additional therapeutic agents, that is administered in an amountsufficient to effect beneficial or desired results.

In some specific aspects, the therapeutic agent is a combinedcomposition comprising any inositol phosphate of the present disclosureand at least an additional therapeutic agent (see, e.g., TABLE 1) or acombination thereof.

The term therapeutic agent also encompasses prophylactic, diagnostic, orimaging agents comprising an inositol phosphate of the presentdisclosure, wherein the therapeutic agent is administered, e.g.,parenterally or topically. Therapeutic agents of the present disclosureinclude not only agents that treat ectopic calcifications, but alsoagents that can ameliorate and/or prevent any symptom associated withthe presence of a calcification. Thus, as defined herein, the termtherapeutic agent would include, for example, agents that can reduce orsuppress inflammation, agent that increase the patient's mobility, andagents that reduce pain.

Target tissue: As used herein “target tissue” refers to any one or moretissue types of interest in which the delivery of a therapeutic and/orprophylactic agent comprising an inositol phosphate of the presentdisclosure would result in a desired biological and/or pharmacologicaleffect. Examples of target tissues of interest include specific tissues,organs, and systems or groups thereof. In particular applications, thetarget tissue can be subcutaneous tissue.

Topical administration: As used herein, the term “topicaladministration” refers to any administration of a composition comprisingan inositol phosphate of the present disclosure by the local route, forexample over the skin, an orifice, or a mucous membrane. Topicaladministration as used herein, includes the cutaneous, aural, nasal,vaginal, urethral, and rectal routes of administration.

Treating, treatment, therapy: As used herein, the terms “treating” or“treatment” or “therapy” refer to partially or completely alleviating,ameliorating, improving, relieving, delaying onset of, inhibitingprogression of, reducing severity of, reducing incidence of one or moresymptoms or features of disease, or any combination thereof. Forexample, “treating” calciphylaxis can refer, e.g., to inhibitingcalcification, reducing the size of calcification, increasing survival,increasing mobility, reducing pain, or any combination thereof.

A treatment comprising an inositol phosphate of the present disclosurecan be administered to a subject who does not exhibit signs of adisease, disorder, and/or condition, and/or to a subject who exhibitsonly early signs of a disease, disorder, and/or condition for thepurpose of, e.g., (i) decreasing the risk of developing a pathologyassociated with the disease, disorder, and/or condition, (ii) delayingthe onset of the disease, disorder, and/or condition, or a pathologyassociated with said disease, disorder, and/or condition, or (iii)mitigating the symptoms and/or sequels of the disease, disorder, and/orcondition or a pathology associated with said disease, disorder, and/orcondition.

Thus, in general, the term “treatment” refers to countering the effectscaused as a result of the disease or pathological condition of interestin a subject including (i) inhibiting the disease or pathologicalcondition, in other words, slowing or stopping the development orprogression thereof; (ii) relieving the disease or pathologicalcondition, in other words, causing said disease or pathologicalcondition, or the symptoms thereof, to regress; (iii) stabilizing thedisease or pathological condition, and (iv) any combination thereof.

ug, uM uL: As used herein, the terms “ug,” “uM,” and “uL” are usedinterchangeably with “μg,” “μM,” and “μL” respectively.

II. Treatment of Ectopic Calcifications

The present disclosure provides methods to treat and/or prevent ectopiccalcifications, e.g., calciphylaxis calcifications, and/or theconsequences thereof in a subject in need thereof comprisingadministering at least one dose of an inositol phosphate of the presentdisclosure (e.g., inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in a dosage of about 5 mg to 10 mgper kg per day to the subject (e.g., a dosage of about 6 mg to about 9mg/kg/day, such as 6 mg/kg/day or 9 mg/kg/day), at least one per week(e.g., once, twice, or three times per week), for a variable period oftime (e.g., from about 1 week to about 32 weeks) wherein theadministration of the dosage effectively treats and/or prevents ectopiccalcification and/or the consequences thereof in the subject.

In the context of the present disclosure, the term “inositol phosphate”as well as the terms “inositol phosphate analog” or “inositol phosphatederivative” refer to compounds encompassed by formula I, the compoundsdisclosed in Section III of the present disclosure, the compoundsdisclosed in Section III incorporating one or more heterologous moietiesdisclose in Section IV, as well as compounds disclosed in the patentsand patents application referenced therein, which are hereinincorporated by reference in their entireties.

The compounds of the present disclosure do no encompass otherphosphate-containing compounds known in the art such as sodiumhexametaphosphate, sodium polyphosphate (Graham salts), orpyrophosphate.

As used herein, the term “inositol phosphate” (and grammatical variantsthereof) refers to a compound with an inositol ring and one, two, three,four, five, or six phosphate groups, or a combination thereof.Myo-inositol hexaphosphate (IP6) is an exemplary inositol phosphate ofthe present disclosure. In some aspects, the inositol phosphate is pure(e.g., over 99% of the inositol phosphate species are the same species,for example, IP6) or substantially pure (e.g., at least 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98% or 99% of the inositol phosphate speciesare the same species, for example, IP6). In some aspects, the inositolphosphate is a mixture, e.g., comprising variable amounts of IP1, IP2,IP3, IP4, IP5, and IP6. In some aspects, the inositol phosphate is aracemic mixture.

A used herein, the term “inositol phosphate analog” (and grammaticalvariants thereof) refers to a compound that has a ring with differentnumber of carbons with respect to an inositol ring (i.e., 5 or 7carbons), and/or has at least one sulfate or thiophosphate group. Forexample, a compound comprising a ring with 5, 6, or 7 carbons and atleast one phosphate, sulfate, or thiophosphate group would be consideredan inositol phosphate analog.

As used herein, the term “inositol phosphate derivative” (andgrammatical variants thereof) refers to an “inositol phosphate” or“inositol phosphate analog” which has been derivatized with aheterologous moiety (i.e., a group that is not a phosphate, a sulfate,or a thiophosphate). For example, an inositol pentasulfate comprising apolyethylene glycol heterologous moiety, or a myo-inositol hexaphosphatecomprising a polyglycerol heterologous moiety would be consideredinositol phosphate derivatives.

A used herein, the term “heterologous moiety” (and grammatical variantsthereof) refers to a group or substituent in a inositol phosphatederivative which is not a phosphate, a sulfate, or a thiophosphate, andconfers a desirable property to such compound. For example, aheterologous moiety (e.g., a polyglycerol or a polyethyleneglycol) canincrease the solubility of the compound. In some aspects, a heterologousmoiety can confer multiple desirable properties; e.g., polyglycerol andpolyethyleneglycol can both increase the solubility of a compound andreduce the clearance rate of the compound.

The terms “inositol phosphate of the disclosure” and “inositol phosphateof the present disclosure,” as used herein, and grammatical variantsthereof, is a generic term encompassing “inositol phosphate,” “inositolphosphate analog,” “inositol phosphate derivative,” and combinationsthereof. In some aspects, the term “inositol phosphate of the presentdisclosure” encompasses compositions comprising an “inositol phosphate,”an “inositol phosphate analog,” an “inositol phosphate derivative,” or acombination thereof, and at least one additional therapeutic agent (see,e.g., TABLE 1).

Compounds of the present disclosure comprising a ring with 5, 6, or 7carbons and at least one sulfate, or thiophosphate group but without aphosphate group would still be considered an “inositol phosphate analog”or an “inositol phosphate analog” in the context of the presentdisclosure. Thus, the term “inositol phosphate of the presentdisclosure” encompasses not only phosphate-containing compounds but alsocompounds without phosphate groups that comprise a ring with 5, 6, or 7carbons and at least one sulfate, or thiophosphate group.

Representative inositol phosphates of the present disclosure arepresented in FIGS. 8-13. FIG. 10 present numerous examples of inositolphosphates, all of them in the myo conformation. Besides myo-inositol,the other naturally occurring stereoisomers of inositol are scyllo-,muco-, 1D-chiro-, 1L-chiro-, neo-inositol, allo-, epi-, andcis-inositol. As their names denote, 1L- and 1D-chiro inositol are theonly pair of inositol enantiomers, but they are enantiomers of eachother, not of myo-inositol. It is to be understood that any exemplaryinositol phosphate presented in the disclosure is not limited to therepresentative conformation displayed. Thus, for example, the examplespresented in FIG. 10 would also encompass the corresponding equivalentsin scyllo-, muco-, 1D-chiro-, 1L-chiro-, neo-inositol, allo-, epi-, andcis-inositol conformations. In its most stable conformation, themyo-inositol isomer assumes the chair conformation, which moves themaximum number of hydroxyls to the equatorial position, where they arefarthest apart from each other. In this conformation, the natural myoisomer has a structure in which five of the six hydroxyls (the first,third, fourth, fifth, and sixth) are equatorial, whereas the secondhydroxyl group is axial.

As used herein, the terms “dose” or “dose of the present disclosure”refers to a total amount, e.g., in grams or grams/kg, of an inositolphosphate of the present disclosure that would be administered to asubject in need thereof over a 24 hour period.

In the context of the present disclosure, the terms “dosage” or “dosageof the present disclosure” refer to a dose of inositol phosphate of thepresent disclosure administered to a subject over a period of time.

A dose can be calculated using the accepted standard weight of asubject. For example, ideal body weight (IBW) is estimated as follows:IBW (kg)=50+2.3 kg for each inch over 5 feet (males); IBW (kg)=45.5+2.3kg for each inch over 5 feet (females). Thus, for example, a dose ofinositol hexaphosphate administered as part of a regimen comprising theadministration of a dosage of 5 mg/kg per day to a subject, assuming anideal body weight of 60 kg, would consist of 300 mg of inositolhexaphosphate. For example, dosages can be adjusted based on thesubjects age, weight, body surface, renal clearance, sex, pathologicalstate, route of administration, concurrent administration of one or moreother drugs, and a wide variety of physiologic and psychological factorsusing methods known in the art. See, e.g., Pan et al. (2016) PatientPrefer Adherence 10: 549-560; Pai et al. (2012) Pharmacotherapy32:856-868; Hacker et al. (2009) “Pharmacology: Principles andPractice,” Academic Press; and references cited therein, all of whichare herein incorporated by reference in their entireties.

The term “mg/kg” as used herein refers to mg of an inositol phosphate ofthe present disclosure per kg of the body mass (body weight) of thesubject.

In general, the effective dose of an inositol phosphate of the presentdisclosure to be administered according to the methods disclosed hereinwill depend, for example, on the relative efficacy of the compoundconcerned, the severity of the disorder treated, and the weight of thesubject. In some aspects, the dose of a inositol phosphate of thepresent disclosure to be administered to a subject can be calculatedbased, e.g., on its capacity to inhibit crystallization, compared to areference compound (e.g., myo-inositol hexaphosphate).

For example, if a given inositol phosphate of the present disclosure hasa capacity to inhibit crystallization equivalent to the capacity toinhibit crystallization of myo-inositol hexaphosphate, the same dosewould be generally used. Conversely, if a given inositol phosphate ofthe present disclosure has a capacity to inhibit crystallization that is50% of the capacity to inhibit crystallization of myo-inositolhexaphosphate, a dose that is two-fold the dose of myo-inositolhexaphosphate could be generally used. In other words, the estimateddose of a inositol phosphate of the present disclosure with respect to amyo-inositol hexaphosphate dose would be the reciprocal value of theratio between their respective capacities to inhibit crystallization (orother measurable property related to the efficacy of the inositolphosphate of the present disclosure to treat ectopic calcifications).Accordingly,

Dose_(compound x)=Dose_(IP6)×1/(Property_(compound x)/Property_(IP6)),

wherein Property can be, e.g., capacity to inhibit hydroxyapatitecrystallization, capacity to inhibit nucleation, or capacity to reduce,inhibit, or prevent any symptom associated with the ectopiccrystallization, e.g., a calciphylaxis calcification.

In some aspects, the measurement of the capacity to inhibitcrystallization of an inositol phosphate of the present disclosure isconducted in vitro. In other aspects, the measurement of the capacity toinhibit crystallization of an inositol phosphate of the presentdisclosure is conducted in vivo.

In some aspects, the inositol phosphate of the present disclosurecomprises a compound of formula I, a pharmaceutically acceptable saltthereof, or a combination thereof:

wherein

-   (i) R₁, R₃, R₅, R₇, R₉ and R₁₁ independently represent OH, a    compound of formula II, or a compound of formula III, or a compound    for formula IV:

-   (ii) R₂, R₄, R₆, R₈, R₁₀, R₁₂ and R₁₃ represent H;-   (iii) at least one of R₁, R₃, R₅, R₇, R₉ and R₁₁ represents a    compound of formula II, formula III or formula IV, and-   (iv) zero, one, or two of R₁, R₃, R₅, R₇, R₉ and R₁₁ represent a    heterologous moiety.

In some aspects, the dose of inositol phosphate of the presentdisclosure comprises from about 5 mg/kg to about 10 mg/kg of an inositolphosphate, an inositol phosphate analog, an inositol phosphatederivative, or combination thereof, with the proviso that, when theinositol phosphate is myo-inositol hexaphosphate, the dose is not equalto 5 mg/kg or 10 mg/kg. In some aspects, when the disease or conditiontreated or prevented is related to chronic kidney disease (CKD), forexample, calciphylaxis in CKD patients (e.g., stage 5 CKD patients), thedose is not equal to 5 mg/kg or 10 mg/kg. In some aspects, when thedosage regimen comprises daily non-bolus dose administration for atleast 14 days, the dose is not equal to 5 mg/kg or 10 mg/kg.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate) is between about 5.0 mg/kgand about 6.0 mg/kg, between about 6.0 mg/kg and about 7.0 mg/kg,between about 7.0 mg/kg and about 8.0 mg/kg, between about 8.0 mg/kg andabout 9.0 mg/kg, or between about 9.0 mg/kg and about 10.0 mg/kg.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate) is between about 5.0 mg/kgand about 5.5 mg/kg, between about 5.5 mg/kg and about 6.0 mg/kg,between about 6.0 mg/kg and about 6.5 mg/kg, between about 6.5 mg/kg andabout 7.0 mg/kg, between about 7.0 mg/kg and about 7.5 mg/kg, betweenabout 7.5 mg/kg and about 8.0 mg/kg, between about 8.0 mg/kg and about8.5 mg/kg, between about 8.5 mg/kg and about 9.0 mg/kg, between about9.0 mg/kg and about 9.5 mg/kg, or between about 9.5 mg/kg and about 10.0mg/kg.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate) is between about 5.0 mg/kgand about 7.0 mg/kg, between about 6.0 mg/kg and about 8.0 mg/kg,between about 7.0 mg/kg and about 9.0 mg/kg, between about 8.0 mg/kg andabout 10.0 mg/kg, between about 5.0 mg/kg and about 8 mg/kg, betweenabout 6.0 mg/kg and about 9.0 mg/kg, between 7.0 mg/kg and about 10.0mg/kg, between about 5.0 mg/kg and about 9 mg/kg, or between about 6.0mg/kg and about 10.0 mg/kg.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate) is about 5.1 mg/kg, about5.2 mg/kg, about 5.3 mg/kg, about 5.4 mg/kg, about 5.5 mg/kg, about 5.6mg/kg, about 5.7 mg/kg, about 5.8 mg/kg, about 5.9 mg/kg, about 6.0mg/kg, about 6.1 mg/kg, about 6.2 mg/kg, about 6.3 mg/kg, about 6.4mg/kg, about 6.5 mg/kg, about 6.6 mg/kg, about 6.7 mg/kg, about 6.8mg/kg, about 6.9 mg/kg, about 7.0 mg/kg, about 7.1 mg/kg, about 7.2mg/kg, about 7.3 mg/kg, about 7.4 mg/kg, about 7.5 mg/kg, about 7.6mg/kg, about 7.7 mg/kg, about 7.8 mg/kg, about 7.9 mg/kg, about 8.0mg/kg, about 8.1 mg/kg, about 8.2 mg/kg, about 8.3 mg/kg, about 8.4mg/kg, about 8.5 mg/kg, about 8.6 mg/kg, about 8.7 mg/kg, about 8.8mg/kg, about 8.9 mg/kg, about 9.0 mg/kg, about 9.1 mg/kg, about 9.2mg/kg, about 9.3 mg/kg, about 9.4 mg/kg, about 9.5 mg/kg, about 9.6mg/kg, about 9.7 mg/kg, about 9.8 mg/kg, about 9.9 mg/kg, or about 10mg/kg.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate) is between about 5.1 mg/kgand about 10 mg/kg, between about 5.2 mg/kg and about 10 mg/kg, betweenabout 5.3 mg/kg and about 10 mg/kg, between about 5.4 mg/kg and about 10mg/kg, between about 5.5 mg/kg and about 10 mg/kg, between about 5.6mg/kg and about 10 mg/kg, between about 5.7 mg/kg and about 10 mg/kg,between about 5.8 mg/kg and about 10 mg/kg, between about 5.9 mg/kg andabout 10 mg/kg, between about 6.0 mg/kg and about 10 mg/kg, betweenabout 6.1 mg/kg and about 10 mg/kg, between about 6.2 mg/kg and about 10mg/kg, between about 6.3 mg/kg and about 10 mg/kg, between about 6.4mg/kg and about 10 mg/kg, between about 6.5 mg/kg and about 10 mg/kg,between about 6.6 mg/kg and about 10 mg/kg, between about 6.7 mg/kg andabout 10 mg/kg, between about 6.8 mg/kg and about 10 mg/kg, betweenabout 6.9 mg/kg and about 10 mg/kg, between about 7.0 mg/kg and about 10mg/kg, between about 7.1 mg/kg and about 10 mg/kg, between about 7.2mg/kg and about 10 mg/kg, between about 7.3 mg/kg and about 10 mg/kg,between about 7.4 mg/kg and about 10 mg/kg, between about 7.5 mg/kg andabout 10 mg/kg, between about 7.6 mg/kg and about 10 mg/kg, betweenabout 7.7 mg/kg and about 10 mg/kg, between about 7.8 mg/kg and about 10mg/kg, between about 7.9 mg/kg and about 10 mg/kg, between about 8.0mg/kg and about 10 mg/kg, between about 8.1 mg/kg and about 10 mg/kg,between about 8.2 mg/kg and about 10 mg/kg, between about 8.3 mg/kg andabout 10 mg/kg, between about 8.4 mg/kg and about 10 mg/kg, betweenabout 8.5 mg/kg and about 10 mg/kg, between about 8.6 mg/kg and about 10mg/kg, between about 8.7 mg/kg and about 10 mg/kg, between about 8.8mg/kg and about 10 mg/kg, between about 8.9 mg/kg and about 10 mg/kg,between about 9.0 mg/kg and about 10 mg/kg, between about 9.1 mg/kg andabout 10 mg/kg, between about 9.2 mg/kg and about 10 mg/kg, betweenabout 9.3 mg/kg and about 10 mg/kg, between about 9.4 mg/kg and about 10mg/kg, between about 9.5 mg/kg and about 10 mg/kg, between about 9.6mg/kg and about 10 mg/kg, between about 9.7 mg/kg and about 10 mg/kg,between about 9.8 mg/kg and about 10 mg/kg, between about 9.9 mg/kg andabout 10 mg/kg, or between about 10 mg/kg and about 10 mg/kg.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate) is between about 5.0 mg/kgand about 5.1 mg/kg, between about 5.0 mg/kg and about 5.2 mg/kg,between about 5.0 mg/kg and about 5.3 mg/kg, between about 5.0 mg/kg andabout 5.4 mg/kg, between about 5.0 mg/kg and about 5.5 mg/kg, betweenabout 5.0 mg/kg and about 5.6 mg/kg, between about 5.0 mg/kg and about5.7 mg/kg, between about 5.0 mg/kg and about 5.8 mg/kg, between about5.0 mg/kg and about 5.9 mg/kg, between about 5.0 mg/kg and about 6.0mg/kg, between about 5.0 mg/kg and about 6.1 mg/kg, between about 5.0mg/kg and about 6.2 mg/kg, between about 5.0 mg/kg and about 6.3 mg/kg,between about 5.0 mg/kg and about 6.4 mg/kg, between about 5.0 mg/kg andabout 6.5 mg/kg, between about 5.0 mg/kg and about 6.6 mg/kg, betweenabout 5.0 mg/kg and about 6.7 mg/kg, between about 5.0 mg/kg and about6.8 mg/kg, between about 5.0 mg/kg and about 6.9 mg/kg, between about5.0 mg/kg and about 7.0 mg/kg, between about 5.0 mg/kg and about 7.1mg/kg, between about 5.0 mg/kg and about 7.2 mg/kg, between about 5.0mg/kg and about 7.3 mg/kg, between about 5.0 mg/kg and about 7.4 mg/kg,between about 5.0 mg/kg and about 7.5 mg/kg, between about 5.0 mg/kg andabout 7.6 mg/kg, between about 5.0 mg/kg and about 7.7 mg/kg, betweenabout 5.0 mg/kg and about 7.8 mg/kg, between about 5.0 mg/kg and about7.9 mg/kg, between about 5.0 mg/kg and about 8.0 mg/kg, between about5.0 mg/kg and about 8.1 mg/kg, between about 5.0 mg/kg and about 8.2mg/kg, between about 5.0 mg/kg and about 8.3 mg/kg, between about 5.0mg/kg and about 8.4 mg/kg, between about 5.0 mg/kg and about 8.5 mg/kg,between about 5.0 mg/kg and about 8.6 mg/kg, between about 5.0 mg/kg andabout 8.7 mg/kg, between about 5.0 mg/kg and about 8.8 mg/kg, betweenabout 5.0 mg/kg and about 8.9 mg/kg, between about 5.0 mg/kg and about9.0 mg/kg, between about 5.0 mg/kg and about 9.1 mg/kg, between about5.0 mg/kg and about 9.2 mg/kg, between about 5.0 mg/kg and about 9.3mg/kg, between about 5.0 mg/kg and about 9.4 mg/kg, between about 5.0mg/kg and about 9.5 mg/kg, between about 5.0 mg/kg and about 9.6 mg/kg,between about 5.0 mg/kg and about 9.7 mg/kg, between about 5.0 mg/kg andabout 9.8 mg/kg, between about 5.0 mg/kg and about 9.9 mg/kg, or betweenabout 5.0 mg/kg and about 10 mg/kg.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate) is administered oncedaily, i.e., as a single daily dose. In some aspects, the daily dose canbe subdivided into smaller doses and administered separately.Accordingly, in some aspect, the total daily dose can be subdivided into2, 3, 4 or more sub-doses, i.e., multiple daily doses.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate) is administered at leastonce a week. In some aspects, the dose of inositol phosphate of thepresent disclosure (e.g., myo-inositol hexaphosphate) is administered atleast 2, at least 3, at least 4, at least 5, at least 6 or at least 7times per week.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate) is administered for atleast one week. In some aspects, the dose of inositol phosphate of thepresent disclosure is administered for about 2 weeks, about 3 weeks,about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks,about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks,about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks,about 31 or about 32 weeks.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate) is administered for atleast 1 weeks, at least 2 weeks, at least 3 weeks, at least 4 weeks, atleast 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, atleast 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks,at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, atleast 24 weeks, at least 25 weeks, at least 26 weeks, at least 27 weeks,at least 28 weeks, at least 29 weeks, least 30 weeks, at least 31 weeks,or at least 32 weeks.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate) is administered for 1 weekto 4 weeks, for 1 week to 8 weeks, for 1 week to 12 weeks, for 1 week to16 weeks, for 1 week to 20 weeks, for 1 week to 24 weeks, for 1 week to28 weeks, for 1 week to 32 weeks, for 4 weeks to 8 weeks, for 4 weeks to12 weeks, for 4 weeks to 16 weeks, for 4 weeks to 20 weeks, for 4 weeksto 24 weeks, for 4 weeks to 28 weeks, for 4 weeks to 32 weeks, for 8weeks to 12 weeks, for 8 weeks to 16 weeks, for 8 weeks to 20 weeks, for8 weeks to 24 weeks, for 8 weeks to 28 weeks, for 8 weeks to 32 weeks,for 12 weeks to 16 weeks, for 12 weeks to 20 weeks, for 12 weeks to 24weeks, for 12 weeks to 28 weeks, for 12 weeks to 32 weeks, for 16 weeksto 20 weeks, for 16 weeks to 24 weeks, for 16 weeks to 28 weeks, for 16weeks to 32 weeks, for 20 weeks to 24 weeks, for 20 weeks to 28 weeks,for 20 weeks to 32 weeks, for 24 weeks to 28 weeks, for 24 weeks to 32weeks, or for 28 weeks to 32 weeks.

In a particular aspect, the dose of inositol phosphate of the presentdisclosure (e.g., a as 6 mg/kg/day or 9 mg/kg/day dose of myo-inositolhexaphosphate) is administered 3 times per week. In a particular aspect,the dose of inositol phosphate of the present disclosure (e.g., a as 6mg/kg/day or 9 mg/kg/day dose of myo-inositol hexaphosphate) isadministered 3 times per week for at least 12 weeks.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 10,000μg/mL and about 100,000 μg/mL. In one specific aspect, the concentrationof inositol phosphate of the present disclosure (e.g., myo-inositolhexaphosphate or an analog or derivative thereof, or a combinationthereof) in each dose is between about 20,000 μg/mL and about 90,000μg/mL.

In one specific aspect, the concentration of inositol phosphate of thepresent disclosure (e.g., myo-inositol hexaphosphate or an analog orderivative thereof, or a combination thereof) in each dose is about20,000 μg/mL. In another specific aspect, the concentration of inositolphosphate of the present disclosure (e.g., inositol hexaphosphate or ananalog or derivative thereof, or a combination thereof) in each dose isabout 30,000 μg/mL. In yet another specific aspect, the concentration ofinositol phosphate of the present disclosure (e.g., inositolhexaphosphate or an analog or derivative thereof, or a combinationthereof) in each dose is about 90,000 μg/mL.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is about 10,000 μg/mL,about 20,000 μg/mL, about 30,000 μg/mL, about 40,000 μg/mL, about 50,000μg/mL, about 60,000 μg/mL, about 70,000 μg/mL, about 80,000 μg/mL, about90,000 or about 100,000 μg/mL of inositol phosphate of the presentdisclosure.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 20,000μg/mL and about 100,000 μg/mL, between about 30,000 μg/mL and about100,000 μg/mL, between about 40,000 μg/mL and about 100,000 μg/mL,between about 50,000 μg/mL and about 100,000 μg/mL, between about 60,000μg/mL and about 100,000 μg/mL, between about 70,000 μg/mL and about100,000 μg/mL, between about 80,000 μg/mL and about 100,000 μg/mL, orbetween about 90,000 μg/mL and about 100,000 μg/mL of inositol phosphateof the present disclosure.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 10,000μg/mL and about 20,000 μg/mL, between about 10,000 μg/mL and about30,000 μg/mL, between about 10,000 μg/mL and about 40,000 μg/mL, betweenabout 10,000 μg/mL and about 50,000 μg/mL, between about 10,000 μg/mLand about 60,000 μg/mL, between about 10,000 μg/mL and about 70,000μg/mL, between about 10,000 μg/mL and about 80,000 μg/mL, or betweenabout 10,000 μg/mL and about 90,000 μg/mL of inositol phosphate of thepresent disclosure.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 10,000μg/mL and about 20,000 μg/mL, between about 20,000 μg/mL and about30,000 μg/mL, between about 30,000 μg/mL and about 40,000 μg/mL, betweenabout 40,000 μg/mL and about 50,000 μg/mL, between about 50,000 μg/mLand about 60,000 μg/mL, between about 60,000 μg/mL and about 70,000μg/mL, between about 70,000 μg/mL and about 80,000 μg/mL, between about80,000 μg/mL and about 90,000 μg/mL, or between about 90,000 μg/mL andabout 100,000 μg/mL of inositol phosphate of the present disclosure.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 10,000μg/mL and about 30,000 μg/mL, between about 20,000 μg/mL and about40,000 μg/mL, between about 30,000 μg/mL and about 50,000 μg/mL, betweenabout 40,000 μg/mL and about 60,000 μg/mL, between about 50,000 μg/mLand about 70,000 μg/mL, between about 60,000 μg/mL and about 80,000μg/mL, between about 70,000 μg/mL and about 90,000 μg/mL, or betweenabout 80,000 μg/mL and about 100,000 μg/mL of inositol phosphate of thepresent disclosure.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 10,000μg/mL and about 40,000 μg/mL, between about 20,000 μg/mL and about50,000 μg/mL, between about 30,000 μg/mL and about 60,000 μg/mL, betweenabout 40,000 μg/mL and about 70,000 μg/mL, between about 50,000 μg/mLand about 80,000 μg/mL, between about 60,000 μg/mL and about 90,000μg/mL, or between about 70,000 μg/mL and about 100,000 μg/mL of inositolphosphate of the present disclosure.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 10,000μg/mL and about 50,000 μg/mL, between about 20,000 μg/mL and about60,000 μg/mL, between about 30,000 μg/mL and about 70,000 μg/mL, betweenabout 40,000 μg/mL and about 80,000 μg/mL, between about 50,000 μg/mLand about 90,000 μg/mL, or between about 60,000 μg/mL and about 100,000μg/mL of inositol phosphate of the present disclosure.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 10,000μg/mL and about 60,000 μg/mL, between about 20,000 μg/mL and about70,000 μg/mL, between about 30,000 μg/mL and about 80,000 μg/mL, betweenabout 40,000 μg/mL and about 90,000 μg/mL, or between about 50,000 μg/mLand about 100,000 μg/mL of inositol phosphate of the present disclosure.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 10,000μg/mL and about 55,000 μg/mL, or between about 55,000 μg/mL and about100,000 μg/mL of inositol phosphate of the present disclosure.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 12.5 mMand about 135 mM.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 12.5 mMand about 125 mM. In some aspects, the concentration of inositolphosphate of the present disclosure (e.g., myo-inositol hexaphosphate oran analog or derivative thereof, or a combination thereof) in each doseis about 25 mM, about 39 mM or about 114 mM.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is about 12.5 mM, about13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM,about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about24 mM, about 25, about 26 mM, about 27 mM, about 28 mM, about 29 mM,about 30 mM, about 31 mM, about 32 mM, about 33 mM, about 34 mM, about35 mM, about 36 mM, about 37 mM, about 38 mM, about 39 mM, about 40 mM,about 41 mM, about 42 mM, about 43 mM, about 44 mM, about 45 mM, about46 mM, about 47 mM, about 48 mM, about 49 mM, about 50 mM, about 51 mM,about 52 mM, about 53 mM, about 54 mM, about 55 mM, about 56 mM, about57 mM, about 58 mM, about 59 mM, about 60 mM, about 61 mM, about 62 mM,about 63 mM, about 64 mM, about 65 mM, about 66 mM, about 67 mM, about68 mM, about 69 mM, or about 70 mM. about 71 mM, about 72 mM, about 73mM, about 74 mM, about 75 mM, about 76 mM, about 77 mM, about 78 mM,about 79 mM, about 80 mM, about 81 mM, about 82 mM, about 83 mM, about84 mM, about 85 mM, about 86 mM, about 87 mM, about 88 mM, about 89 mM,about 90 mM, 91 mM, about 92 mM, about 93 mM, about 94 mM, about 95 mM,about 96 mM, about 97 mM, about 98 mM, about 99 mM, about 100 mM, about101 mM, about 102 mM, about 103 mM, about 104 mM, about 105 mM, about106 mM, about 107 mM, about 108 mM, about 109 mM, about 110 mM, about111 mM, about 112 mM, about 113 mM, about 114 mM, about 115 mM, about116 mM, about 117 mM, about 118 mM, about 119 mM, about 120 mM, about121 mM, about 122 mM, about 123 mM, about 124 mM, about 125 mM, about126 mM, about 127 mM, about 128 mM, about 129 mM, about 130 mM, about131 mM, about 132 mM, about 133 mM, about 134 mM, or about 135 mM.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 12.5 mMand about 20 mM, between about 20 mM and about 30 mM, between about 30mM and about 40 mM, between about 40 mM and about 50 mM, between about50 mM and about 60 mM, between about 60 mM and about 70 mM, betweenabout 70 mM and about 80 mM, between about 80 mM and about 90 mM,between about 90 mM and about 100 mM, between about 100 mM and about 110mM, between about 110 mM and about 120 mM, between about 120 mM andabout 130 mM, or between about 130 mM and about 135 mM.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 12.5 mMand about 30 mM, between about 20 mM and about 40 mM, between about 30mM and about 50 mM, between about 40 mM and about 60 mM, between about50 mM and about 70 mM, between about 60 mM and about 80 mM, betweenabout 70 mM and about 90 mM, between about 80 mM and about 100 mM,between about 90 mM and about 110 mM, between about 100 mM and about 120mM, or between about 110 mM and about 135 mM.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 12.5 mMand about 40 mM, between about 20 mM and about 50 mM, between about 30mM and about 60 mM, between about 40 mM and about 70 mM, between about50 mM and about 80 mM, between about 60 mM and about 90 mM, betweenabout 70 mM and about 100 mM, between about 80 mM and about 110 mM,between about 90 mM and about 120 mM, or between about 100 mM and about135 mM.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 12.5 mMand about 50 mM, between about 20 mM and about 60 mM, between about 30mM and about 70 mM, between about 40 mM and about 80 mM, between about50 mM and about 90 mM, between about 60 mM and about 100 mM, betweenabout 70 mM and about 110 mM, between about 80 mM and about 120 mM,between about 90 mM and about 130 mM, or between about 100 mM and about135 mM.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 12.5 mMand about 60 mM, between about 20 mM and about 70 mM, between about 30mM and about 80 mM, between about 40 mM and about 90 mM, between about50 mM and about 100 mM, between about 60 mM and about 110 mM, betweenabout 70 mM and about 120 mM, between about 80 mM and about 130 mM, orbetween about 90 mM and about 135 mM.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 12.5 mMand about 135 mM, between about 20 mM and about 135 mM, between about 30mM and about 135 mM, between about 40 mM and about 135 mM, between about50 mM and about 135 mM, between about 60 mM and about 135 mM, betweenabout 70 mM and about 135 mM, between about 80 mM and about 135 mM,between about 90 mM and about 135 mM, between about 100 mM and about 135mM, about 110 mM and about 135 mM, between about 120 mM and about 135mM, or between about 130 mM and about 135 mM.

In some aspects, the concentration of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) in each dose is between about 12.5 mMand about 20 mM, between about 12.5 mM and about 30 mM, between about12.5 mM and about 40 mM, between about 12.5 mM and about 50 mM, betweenabout 12.5 mM and about 60 mM, between about 12.5 mM and about 70 mM,between about 12.5 mM and about 80 mM, between about 12.5 mM and about90 mM, between about 12.5 mM and about 100 mM, between about 12.5 mM andabout 110 mM, about 12.5 mM and about 120 mM, between about 12.5 mM andabout 130 mM, or between about 12.5 mM and about 135 mM.

In some aspects, the dose of inositol phosphate of the presentdisclosure (e.g., myo-inositol hexaphosphate or an analog or derivativethereof, or a combination thereof) can be administered parenterally suchas, for example, intravenously, intraperitoneally, intramuscularly,intra-arterially or subcutaneously. Alternatively, the compound can beadministered as a component of a hemodialysis, hemofiltration, orperitoneal dialysis solution. In some aspects, the parenteraladministration is by bolus injection or by intravenous infusion. In someaspects, the administration is topical.

In some aspects, inositol phosphates of the present disclosure can beadministered by any appropriate method, e.g., a method that provokes anon-bolus type release or effect, such as intravascular (for exampleintravenous) infusion, other parenteral (subcutaneous, subcutaneousdepot, intraperitoneal, intramuscular, intradermal, intrathecal,epidural, spinal or others known to a person skilled in the art),topical (intranasal, inhalation, intravaginal, transdermal or othersknown to a person skilled in the art), enteral (oral, sublingual,rectal, etc.) administrations, oral, spinal, intraperitonealpreparations or others known to a person skilled in the art.

As used herein, “parenteral administration” of a composition comprisingan inositol phosphate of the present disclosure includes any route ofadministration characterized by physical breaching of a tissue of asubject and administration of the composition through the breach in thetissue. Parenteral administration thus includes, but is not limited to,administration of a composition comprising an inositol phosphate of thepresent disclosure by injection of the composition, by application ofthe composition through a surgical incision, by application of thecomposition through a tissue-penetrating non-surgical wound, and thelike. In particular, parenteral administration is contemplated toinclude, but is not limited to, subcutaneous, intravenous,intraperitoneal, intramuscular, intrasternal injection, and kidneydialytic infusion techniques.

In the particular case of patients treated with dialysis, a veryappropriate method of administration consists of an administration (e.g,a non-bolus type administration) of an inositol phosphate of the presentdisclosure via the dialysis apparatus (before or after the filter)instead of directly injecting the inositol phosphate of the presentdisclosure into the patient intravenously. Thus, blood can be treatedwith the inositol phosphate of the present disclosure (e.g.,myo-inositol hexaphosphate) as it leaves the patient and circulatesthrough the dialysis circuit and, when the blood containing the inositolphosphate of the present disclosure returns to the body, the inositolphosphate of the present disclosure has been introduced into the bloodin a manner that presents a series of advantages.

In the case of dialysis patients, administration of an inositolphosphate of the present disclosure (e.g., myo-inositol hexaphosphate)via the dialysis apparatus allows the blood to equilibrate with thedialysis fluid prior to returning to the body; thus, although inositolphosphate of the present disclosure (e.g., myo-inositol hexaphosphate)can sequester ionic calcium, this fact is compensated when the bloodpasses through the dialysis filter thereby eliminating said side effectand significantly improving the safety profile.

As used herein, the terms “prolonged release,” “slow release,” or“non-bolus,” refer to an administration form that slowly releases aninositol phosphate of the present disclosure (e.g., myo-inositolhexaphosphate) into the bloodstream, thus allowing significant levels tobe maintained in plasma for a longer period of time than for a“bolus-type” administration. A bolus-type administration comprises,e.g., fast intravenous injection, for example less than 10 seconds (orless than 20, 30, 40, 50, 60 second), or intravenous infusion over lessthan approximately 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7minutes, 8 minutes, 9 minutes or 10 minutes.

In a particular aspect of the present disclosure, myo-inositolhexaphosphate (or a formulation comprising myo-inositol hexaphosphatesuch as SNF472) is administered intravenously via intravenous infusion.In another particular aspect of the present disclosure, myo-inositolhexaphosphate is administered subcutaneously. In another particularaspect of the present disclosure, myo-inositol hexaphosphate isadministered topically.

In some aspect, when an inositol phosphate of the present disclosure(e.g., myo-inositol hexaphosphate) is administered to a patientundergoing dialysis such administration (e.g., intravenousadministration via infusion) can occur during a dialysis treatment.

In some aspects, the inositol phosphate of the present disclosure (e.g.,myo-inositol hexaphosphate) is administered before a dialysis treatment.In some aspects, the inositol phosphate of the present disclosure isadministered after a dialysis treatment.

In some aspects, the inositol phosphate of the present disclosure (e.g.,myo-inositol hexaphosphate) is administered about 1 hour, about 2 hours,about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours,about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours,about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 25hours, about 26 hours, about 27 hours, about 28 hours, about 29 hours,about 30 hours, about 31 hours, about 32 hours, about 33 hours, about 34hours, about 35 hours, about 36 hours, about 37 hours, about 38 hours,about 39 hours, about 40 hours, about 41 hours, about 42 hours, about 43hours, about 44 hours, about 45 hours, about 46 hours, about 47 our orabout 48 hours before a dialysis treatment.

In some aspects, the inositol phosphate of the present disclosure (e.g.,myo-inositol hexaphosphate) is administered about 1 hour, about 2 hours,about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours,about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours,about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 25hours, about 26 hours, about 27 hours, about 28 hours, about 29 hours,about 30 hours, about 31 hours, about 32 hours, about 33 hours, about 34hours, about 35 hours, about 36 hours, about 37 hours, about 38 hours,about 39 hours, about 40 hours, about 41 hours, about 42 hours, about 43hours, about 44 hours, about 45 hours, about 46 hours, about 47 our orabout 48 hours after a dialysis treatment.

In some aspects, the administration of the dosage of inositol phosphateof the present disclosure (e.g., myo-inositol hexaphosphate) to thesubject inhibits the formation and/or growth of hydroxyapatite crystalsand their deposition in ectopic calcifications. In some aspects, theectopic calcification is, e.g., a calciphylaxis calcification, ametastatic calcification, a dystrophic calcification, an iatrogeniccalcification, an idiopathic calcification, or a subcutaneous ectopicossification.

In some aspects, the consequence of the ectopic calcification is, e.g.,(i) a functional complication, (ii) pain, (iii) a trophic complication,(iv) an infection, or (v) a combination thereof. In some aspects, thefunction complication is, e.g., a limitation of range of motion and/orjoint function. In some aspects, the trophic complication is, e.g.,ischemia and/or a lesion. In some aspects, the lesion is, e.g., necrosisof the cutaneous and/or subcutaneous tissues.

In some aspects, administration of the dosage of inositol phosphate ofthe present disclosure (e.g., myo-inositol hexaphosphate) to the subjectcauses a reduction in lesions, e.g., as determined by the Bates-JensenWound Assessment tool or other methods known in the art. Bates-Jensen(1992), supra. In some aspects, the reduction in lesions comprises,e.g., a reduction in the severity of the lesions, a reduction in thesize of the lesions, and reduction in the duration of the lesions, or acombination thereof. In some aspects, administration of the dosage ofinositol phosphate of the present disclosure to the subject causes animprovement in lesion healing. In some aspects, administration of thedosage of inositol phosphate of the present disclosure to the subjectcauses a reduction in pain.

In some aspects, administration of the dosage of inositol phosphate ofthe present disclosure (e.g., myo-inositol hexaphosphate) to the subjectcauses an improvement on global wound quality of life (QoL) asdetermined by using a validated wound-associated QoL questionnaire orother methods known in the art. Augustin (2017), supra. In some aspects,the subject has end-stage renal disease. In some aspects, the subject ison hemodialysis. In some aspects, subject is human.

The present disclosure also provides a method to treat or preventcalciphylaxis calcification and/or the consequences thereof in a subjectin need thereof comprising administering an intravenous dose ofmyo-inositol hexaphosphate in a dosage of about 6 mg to 9 mg per kg perday to the subject, administered 3 times a week for 12 or 24 weeks,wherein the administration of the dosage effectively treats or preventscalciphylaxis calcification and/or the consequences thereof in thesubject. In some aspects, a dosage of about 7 mg per kg per day isadministered to the subject 3 times a week for 12 or 24 weeks.

The presents disclosure also provides an intravenous dose ofmyo-inositol hexaphosphate in a dosage of about 6 mg to 9 mg per kg perday to the subject, administered 3 times a week for 12 or 24 weeks astaken by a patient in a therapeutically effective amount sufficient totreat or prevent calciphylaxis calcification and/or the consequencesthereof in a subject. In some aspects, a dosage of about 7 mg per kg perday is administered to the subject 3 times a week for 12 or 24 weeks.

The present disclosure also provides a kit or article of manufacturecomprising at least one container comprising a parenteral or topicaldose of an inositol phosphate of the present disclosure and instructionsfor administration according to any method disclosed herein.

III. Inositol Phosphate Compositions

The inositol phosphates of the present disclosure comprise, as discussedabove, compounds of formula I, a pharmaceutically acceptable saltthereof, or a combination thereof:

wherein

-   (i) at least one of R₁, R₃, R₅, R₇, R₉ and R₁₁ independently    represent OH, a compound of formula II, or a compound of formula    III, or a compound for formula IV:

-   (ii) R₂, R₄, R₆, R₈, R₁₀, R₁₂ and R₁₃ represent H;-   (iii) at least one of R₁, R₃, R₅, R₇, R₉ and R₁₁ represents a    compound of formula II, formula III or formula IV, and-   (iv) zero, one, or two of R₁, R₃, R₅, R₇, R₉ and R₁₁ represent a    heterologous moiety.

The formulas disclosed herein are meant to encompass any diastereomer.

In some aspects, at least one of R₁, R₃, R₅, R₇, R₉ and R₁₁independently represents H, —X, —OX, —NHX, —NX₂, —SX, —OSO₃HX, —OSO₃X₂or a compound of formula II, formula III or formula IV, where each Xindependently represents H, C₁₋₃₀ alkyl, C₂₋₃₀ alkynyl or Cy₁, whereC₁₋₃₀ alkyl, C₂₋₃₀ alkenyl and C₂₋₃₀ alkynyl are independentlyoptionally substituted with one or more R₁₄ and where Cy₁ is optionallysubstituted by one or more R₁₅;

Cy₁ represents a carbocyclic or heterocyclic three- to 10-membered ring,which can be saturated, partially unsaturated or aromatic, where saidheterocycle has between one and four heteroatoms selected from amongstO, S and N, where said ring can be bound to the rest of the molecule viaany available C atom and where Cy₁ is optionally fused to between oneand four five- or six-membered rings, each saturated, partiallyunsaturated or aromatic, carbocyclic or heterocyclic, and where saidfused heterocycle can contain one or two heteroatoms selected fromamongst O, N and S; each R₁₃ independently represents H, C₁₋₃₀ alkyl,—NH₂, —NHC₁₋₃₀alkyl or N(C₁₋₃₀alkyl)₂, where each C₁₋₃₀ alkyl isindependently optionally substituted with one or more halogen, —OH, —CNand —NO₂ groups; and each R₁₄ and R₁₅ independently represents —OH,C₁₋₃₀ alkoxy, C₁₋₃₀ alkyithionyl, C₁₋₃₀ acyloxy, phosphate, halogen,trihalo C₁₋₃₀ alkyl, nitrile azide.

In some aspects, each X independently represents H, C₁₋₃₀ alkyl or Cy₁,where C₁₋₃₀ alkyl is optionally substituted by one or more R₁₄ and whereCy₁ is optionally substituted by one or more R₁₅; and each R₁₄ and R₁₅independently represents —OH, C₁₋₃₀ alkoxy, C₁₋₃₀ alkyithionyl, C₁₋₃₀acyloxy, phosphate, halogen, trihaloC₁₋₃₀alkyl, nitrile or azide. Insome aspects, each X represents H, C₁₋₃₀alkyl or Cy₁. In some aspects,each X represents H.

In some aspects, at least one of radicals R₁, R₃, R₅, R₇, R₉ and R₁₁independently represents a compound of formula II, formula III orformula IV, each R₁₃ independently represents H, C₁₋₃₀ alkyl, —NH₂,—NHC₁₋₃₀ alkyl or —N(C₁₋₃₀ alkyl)₂, where each C₁₋₃₀ alkyl isindependently optionally substituted by one or more halogen, —OH, —CNand —NO₂ groups; and R₂, R₄, R₆, R₈, R₁₀ and R₁₂ independently representH.

In another aspect, R₁, R₃, R₅, R₇, R₉ and R₁₁ independently represent acompound of formula II, formula III, or formula IV, each R₁₃independently represents H or C₁₋₃₀alkyl, where each C₁₋₃₀alkyl isindependently optionally substituted by one or more halogen, —OH, —CNand —NO₂ groups; and R₂, R₄, R₆, R₈, R₁₀ and R₁₂ independently representH.

In another aspect, R₁, R₃, R₅, R₇, R₉ and R₁₁ independently represent acompound of formula II, formula III, or formula IV, each R₁₃independently represents H or C₁₋₃₀alkyl; and R₂, R₄, R₆, R₈, R₁₀ andR₁₂ independently represent H.

In another aspect, R₁, R₃, R₅, R₇, R₉ and R₁₁ independently represent acompound of formula II, formula III or formula IV, each R₃ independentlyrepresents H; and R₂, R₄, R₆, R₈, R₁₀ and R₁₂ independently represent H.

In a particular aspect, the compound is inositol hexaphosphate (IP6). Inother aspects, the compound is inositol monophosphate (IP1), inositoldiphosphate (IP2), inositol triphosphate (IP3), inositol tetraphosphate(IP4), or inositol pentaphosphate (IP5). In some aspects, compoundcomprises a combination of IP1, IP2, IP3, IP4, IP6 and IP6. In someaspects, the IP6 can form other inositol phosphates (IP5, IP4, IP3, IP2,IP1) by dephosphorylation in vivo. Inositol is assumed to mean anyisomeric form of the molecule.

The inositol phosphates of the present disclosure also encompasscompounds that are produced a metabolites during physiologicaldephosphorylation (or desulfation or dethiosulfation in the case ofcompounds comprising sulfate or thiophosphate groups).

In some aspects, the compound administered in a dosage according to themethods disclosed herein is a prodrug that after undergoing hydrolysisor other intracellular or extracellular processing yields an inositolphosphate of the present disclosure.

The inositol phosphates of the present disclosure encompass also anycombination of the inositol phosphate, inositol phosphate analogs, andderivatives thereof disclosed herein.

All compounds of formula I contain C—O—P or C—O—S bonds, which providethe compounds with an affinity for calcium-containing crystals and asufficiently labile bond to be hydrolyzed in vivo, thereby preventingirreversible binding to calcium-containing crystals such as thehydroxyapatite (HAP) in bone, which would have a negative impact on boneremodeling, as is the case with bisphosphonates when administered longterm as said compounds contain P—C—P bonds that cannot be hydrolyzed bythe body. At the other extreme are phosphorylated compounds that do notcontain said C—O—P bonds, such as pyrophosphates, the P—O—P bonds ofwhich mean that they are too readily hydrolyzed in the intestine, thusmeaning that only parenteral administration is feasible. The compoundsof the present disclosure, with C—O—P bonds, C—O—S bonds, andcombinations thereof represent an adequate midpoint due to the efficacythereof and the fact that the body presents mechanisms for eliminatingsaid compounds, thus reducing the risk of side effects (e.g., compoundswith P—C—P bonds can present half-lives of several months which in vivo,thereby affecting, e.g., bone remodeling).

The term “alkyl” or “alkyl group” in the context of the presentdisclosure refers to a saturated hydrocarbon moiety, which can belinear, branched, cyclic or cyclic with linear or branched side chains.The term alkyl includes partially unsaturated hydrocarbons such aspropenyl. Examples are methyl, ethyl, n- or isobutyl, n- or cyclohexyl.The term alkyl can extend to alkyl groups linked or bridged by heteroatoms. Hetero atoms in the context of the present invention are nitrogen(N), sulfur (S) and oxygen (O).

An “amine function” or “amine group” is a function NR′R″, with R′ and R″selected independently from hydrogen and C₁-C₅ alkyl. In someembodiments, R′ and R″ are selected from hydrogen and C₁-C₃ alkyl. A“hydroxy function” or “hydroxy group” is OH. A “thiol function” or“thiol group” is SH. A “carboxylic acid function” or “carboxylic acidgroup” is COOH or its anion, COO. A “carboxylic amide” is CONR′R″, withR′ and R″ independently having the meanings indicated above. A “sulfonicacid” is SO₃H. A “sulfonic acid amide” is SO₂NR′R″, with R′ and R″independently having the meanings indicated above.

A “C₁-C₃ alkyl” in the context of the present disclosure refers to asaturated linear or branched hydrocarbon having 1, 2, or 3 carbon atoms,wherein one carbon-carbon bond can be unsaturated and one CH₂ moiety canbe exchanged for oxygen (ether bridge). Non-limiting examples for aC₁-C₃ alkyl are methyl, ethyl, propyl, prop-2-enyl and prop-2-inyl.

A “C₁-C₅ alkyl” in the context of the present disclosure refers to asaturated linear or branched hydrocarbon having 1, 2, 3, 4 or 5 carbonatoms, wherein one or two carbon-carbon bond can be unsaturated and oneCH₂ moiety can be exchanged for oxygen (ether bridge). Non-limitingexamples for a C₁-C₅ alkyl include the examples given for C₁-C₃ alkylabove, and additionally n-butyl, 2-methylpropyl, tert-butyl,3-methylbut-2-enyl, 2-methylbut-3-enyl, 3-methylbut-3-enyl, n-pentyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1,2-dimethylpropyl, but-3-enyl, but-3-inyl and pent-4-inyl.

A “C₃-C₁₀ alkyl” in the context of the present disclosure refers to asaturated linear or branched hydrocarbon having 3, 4, 5, 6, 7, 8, 9 or10 carbon atoms, wherein 1, 2 or 3 carbon-carbon bonds can beunsaturated and one CH₂ moiety can be exchanged for oxygen (etherbridge).

The term “C₁₋₃₀ alkyl,” as a group or part of a group, refers to alinear or branched chain alkyl group containing between 1 and 30 carbonatoms including, amongst others, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, decyl and dodecylgroups.

The term “C₂₋₃₀ alkenyl” refers to a linear or branched alkyl chaincontaining between 2 and 30 carbon atoms and also contains one or moredouble bonds. Examples include, amongst others, ethenyl, 1-propenyl,2-propenyl, isopropenyl 1-butenyl, 2-butenyl, 3-butenyl and1,3-butadienyl.

The term “C₂₋₃₀ alkynyl” refers to a linear or branched alkyl chaincontaining between 2 and 30 carbon atoms and also contains one or moretriple bonds. Examples include, amongst others, ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1,3-butadiynyl.

A “Cy₁ group” refers to a three- to 10-membered carbocyclic orheterocyclic ring that can be saturated, partially unsaturated oraromatic and which is bound to the rest of the molecule via anyavailable C atom. When heterocyclic, Cy₁ contains between one and fourheteroatoms selected from amongst N, O and S. Moreover, Cy₁ canoptionally be fused with up to four five- or six-membered carbocyclic orheterocyclic rings, which can be saturated, partially unsaturated oraromatic. If the fused ring is a heterocycle, said ring contains one ortwo heteroatoms selected from amongst N, O and S. Examples of Cy_(t)include, amongst others, phenyl, naphthyl, thienyl, furyl, pyrrolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl,benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl,benzothiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, azetidinyl and aziridinyl.

A “C₁₋₃₀ alkoxy group,” as a group or part of a group, refers to an—OC₁₋₃₀alkyl group, where the C₁₋₃₀alkyl part has the same meaning asabove. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy and tert-butoxy.

A “C₁₋₃₀ alkylthionyl group” as a group or part of a group refers to an—SOC₁₋₃₀alkyl group, where the C₁₋₃₀alkyl part has the same meaning asabove. Examples include methylthionyl, ethylthionyl, propyithionyl,isopropyithionyl, butylthionyl, isobutyithionyl, see-butylthionyl andtert-butylthionyl.

A “C₁₋₃₀ acyloxy group” as a group or part of a group refers to a—COC₁₋₃₀alkyl group, where the C₁₋₃₀alkyl part has the same meaning asabove. Examples include acetyl, ethanoyl, propanoyl and2,2-diisopropylpentanoyl.

A “halogen radical” or the halo abbreviation thereof refers to fluorine,chlorine, bromine and iodine.

A “trihalo C₁₋₃₀ alkyl group” refers to a group resulting from thesubstitution of three hydrogen atoms of a C₁₋₃₀alkyl group by threehalogen radicals as defined above. Examples include, amongst others,trifluoromethyl, tribromomethyl, trichloromethyl, triiodomethyl,trifluoroethyl, tribromoethyl, trichloroethyl, triiodoethyl,tribromopropyl, trichloropropyl and triiodopropyl.

An “—NHC₁₋₃₀ alkyl group” refers to a group resulting from thesubstitution of one hydrogen atom of an —NH₂ group by a C₁₋₃₀alkyl groupas defined above. Examples include, amongst others, methylamine,ethylamine, propylamine, butylamine and pentylamine.

A “—N(C₁₋₃₀alkyl)₂ group” refers to a group resulting from thesubstitution of two hydrogen atoms of an —NH₂ group by a C₁₋₃₀alkylgroup as defined above. Examples include, amongst others, dimethylamine,diethylamine, diisopropylamine, dibutylamine and diisobutylamine.

The expression “optionally substituted by one or more” signifies thepossibility that a group can be substituted by one or more, e.g., by 1,2, 3 or 4 substituents. In some aspects, a group can be substituted by1, 2 or 3 substituents and even by 1 or 2 substituents provided that thegroup has sufficient positions that can be substituted available. Ifpresent, the substituents can be the same or different and can belocated at any available position.

In some aspects, the inositol phosphates of the present disclosure used,e.g., in the methods and compositions disclosed herein, comprise thecompounds disclosed in International Publication Nos. WO2017098033 andWO2017098047, and U.S. Appl. Publ. No. U.S. Pat. No. 9,358,243B2, all ofwhich are herein incorporated by reference in their entireties. In someaspects, the inositol phosphates of the present disclosure used, e.g.,in the methods and compositions disclosed herein, comprise the compoundsdisclosed in FIGS. 8, 9, 10, 11, 12 and 13.

In some aspects, the inositol phosphates, inositol phosphate analogs,and derivatives thereof used, e.g., in the methods and compositionsdisclosed herein, comprise compounds of formula (V), formula (VI), orformula (VII):

whereineach X independently is selected from OPO₃ ²⁻, OPSO₂ ²⁻, or OSO₃ ⁻;Z is an alkyl chain comprising 1 to 3 carbon and/or hetero atoms,optionally comprising a group X, wherein X is also selected from OPO₃²⁻, OPSO₂ ²⁻, or OSO₃ ⁻; and,R¹ is an optional heterologous moiety (see Section IV below). In someaspects, the molecule comprises more than one heterologous moiety, inwhich case the heterologous moieties can be the same or be different.

In some aspects, Z, as used in formula (V), is CH₂, CHX, CHR¹, CXR¹,CH₂—CH₂, CH₂—CHX, CHX—CHX, CHR¹—CHX, CXR¹—CHX, CHR¹—CH₂, CXR¹—CH₂,CHR¹—CHOH, CH₂—CH₂—CH₂, CH₂—O—CH₂, CHOH—CH₂—CH₂, CHOH—CHOH—CHR¹,CHOH—CHR¹—CHOH, CHX—CH₂—CH₂, CH₂—CHX—CH₂, CHX—CHX—CH₂, CHX—CH₂—CHX orCHX—CHR¹—CHX, wherein X independently is selected from OPO₃ ²⁻, OPSO₂²⁻, and OSO₃ ⁻.

In some aspects, Z, as used in formula (V), is (CHX)_(p)CHX(CHX)_(q);wherein p and q each independently from the other have a value from 0 to2, with the proviso that (p+q) has a value of 0, 1 or 2; one or two orthree X can be a heterologous moiety (e.g., PEG) and the remaining X areindependently selected from OPO₃ ²⁻, OPSO₂ ²⁻, and OSO₃ ⁻. In someaspects, not all X of Z are OPO₃ ²⁻. In some aspects, not all X of Z areOSO₃ ⁻.

In some aspects, one, two, or three of the X in compounds of formula(V), formula (VI), or formula (VII) can be heterologous moiety and theremaining X can independently be selected from OPO₃ ²⁻, OPSO₂ ²⁻, orOSO₃ ⁻.

Formula (V) above describes a five-membered, six-membered, orseven-membered alkyl ring, and the optional heterologous moiety ormoieties is/are attached to one of the carbon atoms forming the ring.

In some aspects, the inositol phosphates, inositol phosphate analogs,and derivatives thereof used, e.g., in the methods and compositionsdisclosed herein, comprise compounds of formula (VIII) or formula (IX):

wherein:

-   (a) X² is OSO₃ ⁻, and X¹, X³, X⁴, X⁵ and X⁶ are independently    selected from OPO₃ ²⁻, OPSO₂ ²⁻ or OSO₃ ⁻;-   (b) X¹, X³ and X⁵ are OPO₃ ²⁻ and X², X⁴ and X⁶ are OSO₃ ⁻;-   (c) X¹, X³ and X⁵ are OSO₃ ⁻ and X², X⁴ and X⁶ are OPO₃ ²⁻;-   (d) X⁴, X⁵ and X⁶ are OSO₃ ⁻ and X¹, X² and X³ are OPO₃ ²⁻;-   (e) X⁴, X⁵ and X⁶ are OPO₃ ²⁻ and X¹, X² and X³ are OSO₃ ⁻;-   (f) X² and X⁵ are OPO₃ ²⁻ and X¹, X³, X⁴, and X⁶ are OPO₃ ⁻;-   (g) X² and X⁵ are OSO₃ ⁻ and X¹, X³, X⁴, and X⁶ are OPO₃ ²⁻;-   (h) X² and X³ are OPO₃ ²⁻ and X¹, X⁴, X⁵, and X⁶ are OSO₃ ⁻; or,-   (i) X² and X³ are OSO₃ ⁻ and X¹, X⁴, X⁵, and X⁶ are OPO₃ ²⁻.

In some aspects, the inositol phosphates of the present disclosure ormetabolites thereof can be detected and/or quantified using the methodsdisclosed in U.S. Pat. No. 9,612,250B2, which is herein incorporated byreference in its entirety. See also, U.S. Pat. Nos. 8,377,909B2 and8,778,912 and U.S. Pat. Appl. Publ. No. US20070066574.

The compounds disclosed herein can be present in any form commonly usedin pharmaceutical technology. Particular aspects include, but are notlimited to, the sodium salt, magnesium salt, potassium salt, ammoniumsalt, free acid, or a mixture of the preceding forms. Otherpharmaceutically acceptable salts are known to the skilled artisan andcan be obtained, inter alia, from Haynes et al. (2005) J. PharmaceuticalSci. 94:2111-2120.

IV. Heterologous Moieties

In some aspects, the inositol phosphate derivatives of the presentdisclosure can comprise at least one heterologous moiety conferring anadvantageous property with respect to a corresponding molecule lackingsuch heterologous moiety or moieties. Exemplary advantageous propertiesthat can be conferred by a heterologous moiety or a combination thereofto an inositol phosphate or inositol phosphate analogs are:

-   (i) increase in solubility;-   (ii) increase or decrease in degradation or metabolisation rate;-   (iii) increase or decrease in plasma half-life;-   (iv) decrease in liver metabolisation rate;-   (v) increase or decrease in renal clearance;-   (vi) decrease in precipitation;-   (vii) increase in shelf life;-   (viii) increase or decrease in rate of permeation through    physiological barriers (e.g., blood-brain barrier, intestinal wall,    peritoneum, vascular walls, skin, etc);-   (ix) thermal stability;-   (x) resistance to phosphatases and/or sulfatases;-   (xi) any combination thereof.

The advantageous properties disclosed above can be evaluated orquantified using methods known in the art without undue experimentation.

In some aspects, the heterologous moiety is, e.g., a polyethylene glycol(PEG), a polyglycerol (PG).

PEG:

In certain aspects, the heterologous moiety comprises a polyethyleneglycol (PEG) characterized by a formula R³—(O—CH₂—CH₂)_(n)— orR³—(O—CH₂—CH₂)_(n)—O— with R³ being hydrogen, methyl or ethyl and nhaving a value from 2 to 200.

In some aspects, n has a value of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101,102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115,116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129,130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143,144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157,158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171,172, 173, 174, 175, 176, 177, 178, 179, 189, 181, 182, 183, 184, 185,186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, or200.

In some aspects, n is between 2 and 10, between 10 and 20, between 20and 30, between 30 and 40, between 40 and 50, between 50 and 60, between60 and 70, between 70 and 80, between 80 and 90, between 90 and 100,between 100 and 110, between 110 and 120, between 120 and 130, between130 and 140, between 140 and 150, between 150 and 160, between 160 and170, between 170 and 180, between 180 and 190, or between 190 and 200.

In some specific aspects, n has a value from 3 to 200, from 3 to 20,from 10 to 30, or from 9 to 45.

In some aspects, the PEG is a branched PEG. Branched PEGs have three toten PEG chains emanating from a central core group.

In certain embodiments, the PEG moiety is a monodisperse polyethyleneglycol. In the context of the present disclosure, a monodispersepolyethylene glycol (mdPEG) is a PEG that has a single, defined chainlength and molecular weight. mdPEGs are typically generated byseparation from the polymerization mixture by chromatography. In certainformulae, a monodisperse PEG moiety is assigned the abbreviation mdPEG.

In some aspects, the PEG is a Star PEG. Star PEGs have 10 to 100 PEGchains emanating from a central core group.

In some aspects, the PEG is a Comb PEGs. Comb PEGs have multiple PEGchains normally grafted onto a polymer backbone.

In certain aspects, the PEG has a molar mass between 100 g/mol and 3000g/mol, particularly between 100 g/mol and 2500 g/mol, more particularlyof approx. 100 g/mol to 2000 g/mol. In certain aspects, the PEG has amolar mass between 200 g/mol and 3000 g/mol, particularly between 300g/mol and 2500 g/mol, more particularly of approx. 400 g/mol to 2000g/mol.

In some aspects, the PEG is PEG₁₀₀, PEG₂₀₀, PEG₃₀₀, PEG₄₀₀, PEG₅₀₀,PEG₆₀₀, PEG₇₀₀, PEG₈₀₀, PEG₉₀₀, PEG₁₀₀₀, PEG₁₁₀₀, PEG₁₂₀₀, PEG₁₃₀₀,PEG₁₄₀₀, PEG₁₅₀₀, PEG₁₆₀₀, PEG₁₇₀₀, PEG₁₈₀₀, PEG₁₉₀₀, PEG₂₀₀₀, PEG₂₁₀₀,PEG₂₂₀₀, PEG₂₃₀₀, PEG₂₄₀₀, PEG₂₅₀₀, PEG₁₆₀₀, PEG₁₇₀₀, PEG₁₈₀₀, PEG₁₉₀₀,PEG₂₀₀₀, PEG₂₁₀₀, PEG₂₂₀₀, PEG₂₃₀₀, PEG₂₄₀₀, PEG₂₅₀₀, PEG₂₆₀₀, PEG₂₇₀₀,PEG₂₈₀₀, PEG₂₉₀₀, or PEG₃₀₀₀. In one particular aspect, the PEG isPEG₄₀₀. In another particular aspect, the PEG is PEG₂₀₀₀.

PG:

In some aspects, the heterologous moiety is a polyglycerol (PG)described by the formula ((R₃—O—(CH₂—CHOH—CH₂O)_(n)—) with R3 beinghydrogen, methyl or ethyl, and n having a value from 3 to 200. In someaspects, n has a value from 3 to 20. In some aspects, n has a value from10 to 30. In some alternatives of these embodiments, n has a value from9 to 45. In some aspects, the heterologous moiety is a branchedpolyglycerol described by the formula (R³—O—(CH₂—CHOR⁵—CH₂—O)_(n)—) withR⁵ being hydrogen or a linear glycerol chain described by the formula(R³—O—(CH₂—CHOH—CH₂—O)_(n)—) and R³ being hydrogen, methyl or ethyl. Insome aspects, the heterologous moiety is a hyperbranched polyglyceroldescribed by the formula (R³—O—(CH₂—CHOR⁵—CH₂—O)_(n)—) with R⁵ beinghydrogen or a glycerol chain described by the formula(R³—O—(CH₂—CHOR⁶—CH₂—O)_(n)—), with R⁶ being hydrogen or a glycerolchain described by the formula (R³—O—(CH₂—CHOR⁷—CH₂—O)_(n)—), with R⁷being hydrogen or a linear glycerol chain described by the formula(R³—O—(CH₂—CHOH—CH₂—O)_(n)—) and R³ being hydrogen, methyl or ethyl.Hyperbranched glycerol and methods for its synthesis are described inOudshorn et al. (2006) Biomaterials 27:5471-5479; Wilms et al. (20100Acc. Chem. Res. 43, 129-41, and references cited therein.

In certain aspects, the PG has a molar mass between 100 g/mol and 3000g/mol, particularly between 100 g/mol and 2500 g/mol, more particularlyof approx. 100 g/mol to 2000 g/mol. In certain aspects, the PG has amolar mass between 200 g/mol and 3000 g/mol, particularly between 300g/mol and 2500 g/mol, more particularly of approx. 400 g/mol to 2000g/mol.

In some aspects, the PG is PG₁₀₀, PG₂₀₀, PG₃₀₀, PG₄₀₀, PG₅₀₀, PG₆₀₀,PG₇₀₀, PG₈₀₀, PG₉₀₀, PG₁₀₀₀, PG₁₁₀₀, PG₁₂₀₀, PG₁₃₀₀, PG₁₄₀₀, PG₁₅₀₀,PG₁₆₀₀, PG₁₇₀₀, PG₁₈₀₀, PG₁₉₀₀, PG₂₀₀₀, PG₂₁₀₀, PG₂₂₀₀, PG₂₃₀₀, PG₂₄₀₀,PG₂₅₀₀, PG₁₆₀₀, PG₁₇₀₀, PG₁₈₀₀, PG₁₉₀₀, PG₂₀₀₀, PG₂₁₀₀, PG₂₂₀₀, PG₂₃₀₀,PG₂₄₀₀, PG₂₅₀₀, PG₂₆₀₀, PG₂₇₀₀, PG₂₈₀₀, PG₂₉₀₀, or PG₃₀₀₀. In oneparticular aspect, the PG is PG₄₀₀. In another particular aspect, the PGis PG₂₀₀₀.

V. Pharmaceutical Compositions

The present disclosure also provides pharmaceutical compositions for usein the methods for the prevention and/or treatment of ectopiccalcifications disclosed herein, wherein the pharmaceutical compositioncomprises at least one inositol phosphate of the present disclosure(e.g., myo-inositol hexaphosphate or an analog or derivative thereof ora combination thereof). In some aspects, the pharmaceutical compositioncomprises an inositol phosphate of the present disclosure alone ortogether with one or more pharmaceutically acceptable excipients orcarriers.

The term “excipient” as used herein refers to a substance which helpsabsorption of the elements of the pharmaceutical composition, stabilizessaid elements, activates or helps preparation of the composition. Thus,examples of excipients used in parenteral formulations include, but arenot limited to, antimicrobial agents (e.g., benzalkonium chloride,metacresol, thimerosal), co-solvents (e.g., ethanol), buffers and pHadjusting factors (e.g., carbonate, citrate, phosphate solutions).

As is the case for the excipient, the “pharmaceutically acceptablevehicle” is a substance used in the composition to dilute any of thecomponents contained therein to a determined volume or weight. Thepharmaceutically acceptable vehicle is an inert substance or a substancewith an analogous action to any of the elements comprising thepharmaceutical composition of the present disclosure. The role of saidvehicle is to allow the incorporation of other elements, allow betterdosing and administration or to provide consistency and shape to thecomposition.

Pharmaceutical compositions can comprise from approximately 1% toapproximately 95% active ingredient (i.e., an inositol phosphate of thepresent disclosure or a combination, alone or in combination, e.g., withone or more therapeutic agents disclosed in TABLE 1). In some aspects,e.g., the pharmaceutical compositions of the present disclosure cancomprise from approximately 20% to approximately 90% active ingredient(i.e., an inositol phosphate of the present disclosure or a combination,alone or in combination, e.g., with one or more therapeutic agentsdisclosed in TABLE 1).

Formulations of a pharmaceutical composition suitable for parenteraladministration comprise the active ingredient, e.g., an inositolphosphate of the present disclosure, combined with a pharmaceuticallyacceptable carrier, such as sterile water or sterile isotonic saline.Such formulations can be prepared, packaged, or sold in a form suitablefor bolus administration or for continuous administration. Injectableformulations can be prepared, packaged, or sold in unit dosage form,such as in ampules or in multi-dose containers containing apreservative. Formulations for parenteral administration include, butare not limited to, suspensions, solutions, emulsions in oily or aqueousvehicles, pastes, and implantable sustained-release or biodegradableformulations. Such formulations can further comprise one or moreadditional ingredients including, but not limited to, suspending,stabilizing, or dispersing agents.

In some aspects, in a formulation for parenteral administration, theactive ingredient, e.g., an inositol phosphate of the presentdisclosure, is provided in dry (i.e., powder or granular) form forreconstitution with a suitable vehicle (e.g., sterile pyrogen-freewater) prior to parenteral administration of the reconstitutedcomposition.

The pharmaceutical compositions can be prepared, packaged, or sold inthe form of a sterile injectable aqueous or oily suspension or solution.This suspension or solution can be formulated according to the knownart, and may comprise, in addition to the active ingredient, e.g., aninositol phosphate of the present disclosure, additional ingredientssuch as the dispersing agents, wetting agents, or suspending agentsdescribed herein. Such sterile injectable formulations can be preparedusing a non-toxic parenterally-acceptable diluent or solvent, such aswater or 1,3-butanediol, for example. Other acceptable diluents andsolvents include, but are not limited to, Ringer's solution, isotonicsodium chloride solution, and fixed oils such as synthetic mono- ordi-glycerides.

Other parentally-administrable formulations which are useful includethose which comprise the active ingredient in microcrystalline form, ina liposomal preparation, or as a component of a biodegradable polymersystem. Compositions for sustained release or implantation can comprisepharmaceutically acceptable polymeric or hydrophobic materials such asan emulsion, an ion exchange resin, a sparingly soluble polymer, or asparingly soluble salt.

Controlled- or sustained-release formulations of a pharmaceuticalcomposition of the present disclosure can be made using conventionaltechnology. In some cases, the dosage forms to be used can be providedas slow or controlled-release of one or more active ingredients thereinusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, or microspheres or a combination thereof toprovide the desired release profile in varying proportions.

Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the pharmaceutical compositions of the disclosure.Thus, single unit dosage forms suitable for parenteral or topicaladministration, such as injectable solutions, gels, creams, andointments, which are adapted for controlled-release are encompassed bythe present disclosure.

Most controlled-release pharmaceutical products have a common goal ofimproving therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of therapeutic agent being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the therapeutic agent, reduceddosage frequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood level of thetherapeutic agent, and thus can affect the occurrence of side effects.

Most controlled-release formulations are designed to initially releasean amount of therapeutic agent that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of therapeutic agent to maintain this level of therapeuticeffect over an extended period of time. In order to maintain thisconstant level of therapeutic agent in the body, the therapeutic agentmust be released from the dosage form at a rate that will replace theamount of therapeutic agent being metabolized and excreted from thebody.

Controlled-release of an active ingredient can be stimulated by variousinducers, for example pH, temperature, enzymes, water, or otherphysiological conditions or compounds. The term “controlled-releasecomponent” in the context of the present disclosure is defined herein asa compound or compounds, including, but not limited to, polymers,polymer matrices, gels, permeable membranes, liposomes, or microspheresor a combination thereof that facilitates the controlled-release of theactive ingredient.

In certain embodiments, the formulations of the present disclosure canbe, but are not limited to, short-term, rapid-offset, as well ascontrolled, for example, sustained release, delayed release andpulsatile release formulations.

The term sustained release is used in its conventional sense to refer toa therapeutic agent formulation, e.g., a formulation comprising aninositol phosphate of the present disclosure, that provides for gradualrelease of a therapeutic agent over an extended period of time, and thatcan, although not necessarily, result in substantially constant bloodlevels of a therapeutic agent over an extended time period. The periodof time can be as long as a month or more and should be a release whichis longer that the same amount of agent administered in bolus form.

For sustained release, the compounds may be formulated with a suitablepolymer or hydrophobic material which provides sustained releaseproperties to the compounds. As such, the compounds for use the methodof the present disclosure can be administered in the form ofmicroparticles, for example, by injection or in the form of wafers ordiscs by implantation. In certain aspects, the compounds of thedisclosure are administered to a patient, alone or in combination withanother pharmaceutical agent, using a sustained release formulation.

The term delayed release is used herein in its conventional sense torefer to a therapeutic agent formulation that provides for an initialrelease of the therapeutic agent after some delay following therapeuticagent administration. The delay may be from about 10 minutes up to about12 hours. The term pulsatile release is used herein in its conventionalsense to refer to a therapeutic agent formulation that provides releaseof the therapeutic agent in such a way as to produce pulsed plasmaprofiles of the therapeutic agent after administration. The termimmediate release is used in its conventional sense to refer to atherapeutic agent formulation that provides for release of thetherapeutic agent immediately after administration.

As used herein, short-term refers to any period of time up to andincluding about 8 hours, about 7 hours, about 6 hours, about 5 hours,about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40minutes, about 20 minutes, or about 10 minutes and any or all whole orpartial increments thereof after therapeutic agent administration.

As used herein, rapid-offset refers to any period of time up to andincluding about 8 hours, about 7 hours, about 6 hours, about 5 hours,about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40minutes, about 20 minutes, or about 10 minutes, and any and all whole orpartial increments thereof after therapeutic agent administration.

Additional formulations and dosage forms of the compositions of thepresent disclosure include dosage forms as described in U.S. Pat. Nos.6,340,475, 6,488,962, 6,451,808, 5,972,389, 5,582,837, and 5,007,790;U.S. Patent Applications Nos. 20030147952, 20030104062, 20030104053,20030044466, 20030039688, and 20020051820; PCT Applications Nos. WO03/35041, WO 03/35040, WO 03/35029, WO 03/35177, WO 03/35039, WO02/96404, WO 02/32416, WO 01/97783, WO 01/56544, WO 01/32217, WO98/55107, WO 98/11879, WO 97/47285, WO 93/18755, and WO 90/11757, all ofwhich are incorporated herein by reference in their entireties.

Medicaments according to the disclosure are manufactured by methodsknown in the art, especially by conventional mixing, coating,granulating, dissolving or lyophilizing.

The present disclosure also provides a compound or a combination ofcompounds or pharmaceutical formulation according to any of the aboveaspects of the disclosure, in the broadest definition given, or asspecified in any of the aspects presented above, for use as amedicament.

The present disclosure also provides a compound or combination ofcompounds or pharmaceutical formulation according to any of the aboveaspects of the disclosure, in the broadest definition given, or asspecified in any of the aspects presented above, for use in thetreatment and/or prevention of a disease or condition disclosed herein.

The present disclosure also provides a compound or combination ofcompounds or pharmaceutical formulation according to any of the aboveaspects of the disclosure, in the broadest definition given, or asspecified in any of the aspects presented above, for the manufacture ofa medicament for the prevention and/or treatment of a disease orcondition disclosed herein.

VI. Indications

The methods, compositions, pharmaceutical compositions and formulations,articles of manufacture and kits comprising inositol phosphates of thepresent disclosure disclosed herein, can be used to treat and/preventectopic calcifications, and in particular cutaneous or subcutaneouscalcification such as calciphylaxis calcifications, and/or theconsequences thereof in a subject in need thereof.

Cutaneous and subcutaneous calcifications (in general referred to asectopic calcifications) are related to the pathological crystallizationof calcium and arise as complications in numerous diseases. Ectopiccalcifications can be classified into dystrophic, metastatic,idiopathic, or iatrogenic calcifications, or into calciphylaxis.

Dystrophic calcifications result from local tissue abnormalities andgrow in spite of normal plasma calcium and phosphorus levels. The maindiseases that can develop due to these calcifications are: connectivetissue diseases (scleroderma, CREST syndrome, juvenile dermatomyositis,lupus), cutaneous and subcutaneous infections (panniculitis), skintumors (in particular pilomatricoma), certain congenital diseases(Elher-Danlos disease, Werner's syndrome, pseudo xanthoma elasticum).

Metastatic calcifications are the result of a disorder of calcium andphosphate metabolism (hypercalcemia and/or hyperphosphatemia). Alldiseases that cause these disorders can therefore contribute to thedevelopment of calcifications.

Idiopathic calcifications occur without tissue lesions or disorders ofcalcium and phosphate metabolism. The main known diseases in this groupare tumoral calcinosis, scrotal calcifications as well as sub-epidermalcalcified nodules.

Iatrogenic calcifications can occur following the injection of calciumor para-aminosalycylic acid. They have also been described following theuse of calcium chloride saturated electrodes.

Soft tissue calcifications (e.g., cutaneous or subcutaneouscalcifications) can be associated with a disease or pathologicalcondition selected from the group consisting of primaryhyperparathyroidism, vitamin D intoxication, milk drinker's syndrome,hypercalcemia, secondary hyperparathyroidism, renal failure,hyperphosphatemia, in particular genetic hyperphosphatemia, scleroderma,dermatomyositis, in particular the juvenile form, mixed connectivetissue diseases, lupus, CREST syndrome, Elhers-Danlos syndrome, pseudoxanthoma elasticum, Werner's syndrome, late cutaneous porphyria, pseudohypoparathyroidism, pseudo pseudo-hypoparathyroidism, (primary orsecondary) venous or arterial insufficiency, diabetes, scrotalcalcinosis, ossifying myositis, post-traumatic ectopic ossifications andany other disease or pathological condition caused by calcium crystaldeposit(s), in particular of hydroxyapatite or calcium pyrophosphate,e.g., calciphylaxis.

An important concept is that various disorders, including those listedin the previous paragraphs, can be treated by preventing, reducing,slowing or stopping the progression of calcification in the presence ofuremia. The disease related to calcium disorders, or the calcificationinduced by said disease, can already be present when administrationcommences, in order to reduce or stop progression of the disease, or cannot yet be present, in order to prevent the appearance or onset of thedisease.

Calciphylaxis corresponds to the calcification of small sized bloodvessels and of the sub-cutaneous adipose tissue. Calciphylaxis can betreated concurrently with at least the following diseases

-   (i) Hypercalcemia;-   (ii) Hyperphosphatemia;-   (iii) Secondary and tertiary hyperparathyroidism;-   (iv) Hypoparathyroidism; or,-   (v) Any combination thereof.

Further conditions that can benefit from a treatment with the inositolphosphates of the disclosure are, e.g., peripheral arterial disease,critical limb ischemia, general arterial calcification of infancy,aortic stenosis, atherosclerosis, pseudogout, primary hyperoxaluria andpseudoxanthoma elasticum.

In the context of the present disclosure, “peripheral arterial disease”refers to a narrowing of the peripheral arteries to the legs (mostcommonly), stomach, arms, and head. Symptoms include intermittentclaudication (leg pain when walking which resolves with rest), skinulcers, bluish skin, cold skin, or poor nail and hair growth.

In the context of the present disclosure, “critical limb ischemia”refers to a severe obstruction of the arteries which markedly reducesblood flow to the extremities and progresses to the point of severe painand even skin ulcers, sores, or gangrene. Critical limb ischemia is avery severe condition of peripheral artery disease.

In the context of the present disclosure, “pseudogout”, also known as“Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease” or“pyrophosphate arthropathy” refers to a rheumatologic disorder believedto be caused by calcium pyrophosphate crystal accumulation in connectivetissues, particularly joints such as the knee joint.

In the context of the present disclosure, the term “general arterialcalcification of infancy” (GACI) relates to a disorder affecting thecirculatory system that becomes apparent before birth or within thefirst few months of life, and which is characterized by abnormalcalcification of the arteries and thickening of the arterial walls.These changes lead to stenosis and stiffness of the arteries, resultingin heart failure in some affected individuals, with signs and symptomsincluding difficulty breathing, edema, cyanosis, hypertension andcardiomegaly.

VII. Combination Therapies

The present disclosure also provides combination treatments comprisingthe administration of an inositol phosphate of the disclosure and atleast one additional therapeutic agent. Also provided are combinedcompositions comprising an inositol phosphate of the disclosure and atleast one additional therapeutic agent. Thus, a further aspect of thepresent disclosure relates to a composition comprising at least oneinositol phosphate of the disclosure as described above and anothertherapeutic agent.

The term “combination therapy” as used herein refers interchangeably toboth combination treatments according to the methods and dosagesdisclosed herein, and to combined compositions. As used herein the term“combined composition” does not imply the components of the combinedcomposition need to be present together. Consequently, the expressionimplies that the combination is not necessarily a true combination inlight of the physical separation of the components thereof. For example,the components in a combined composition can be applied separately,sequentially, or their application can overlap.

In some aspects, the additional therapeutic agent is selected, e.g.,from the compositions presented in TABLE 1. In some aspects, acombination therapy can comprise an inositol phosphate of the disclosureand a therapeutic agent from TABLE 1. In other aspects, a combinationtherapy can comprise an inositol phosphate of the disclosure and morethan one therapeutic agent from TABLE 1. When more than one therapeuticagent from TABLE 1 is present in a combination therapy, the therapeuticagents from TABLE 1 can belong to the same indication or to differentindications. For example, a combination composition can comprise atreatment (e.g., OPG), a wound healing compound, and a pain managementcompound.

TABLE 1 Exemplary therapeutic agents that can be combined with theinositol phosphates of the present disclosure. Indication Therapeuticagent(s) to combine with compound(s) of the disclosure TreatmentOsteoprotegerin (OPG) Corticosteroids Group A (hydrocortisone,hydrocortisone, methylprednisolone, prednisolone, prednisone,triamcinolone) Group B (amcinonide, budesonide, desonide, fluocinoloneacetonide, fluocinonide, halcinonide, triamcinolone acetonide) Group C(beclometasone, betamethasone, dexamethasone, fluocortolone,halometasone, mometasone) Group D1 (alclometasone dipropionate,betamethasone dipropionate, betamethasone valerate, clobetasolpropionate, clobetasone butyrate, fluprednidene acetate, mometasonefuroate) Group D2 (ciclesonide, cortisone acetate, hydrocortisoneaceponate, hydrocortisone acetate, hydrocortisone buteprate,hydrocortisone butyrate, hydrocortisone valerate, prednicarbate,tixocortol pivalate) Fetuin-alpha Vitamin K Protein C Protein S GlaProtein Matrix (MGP) Hyperbaric medicine ¹Cinacalcet CAS [226256-56-0]²Sevelamer CAS [52757-95-6], lanthanum carbonate, sucroferricoxyhydroxide Bisphosphonates (etidronate, pamidronate), sodiumthiosulfate, other C-O-P compounds Other ectopic calcificationinhibitors Wound Gram positive antibiotics (gloxacillin, amoxicillinplus clavulanic acid, healing piperacillin-tazobactam, daptomycin)Anaerobic germs antibiotics (metronidazole, clindamycin) Pain Analgesicsin general that are not easily dialyzed management Opioids(buprenorphine, fentanyl, methadone) General GBA analogs (gabapentin)analgesia Central pain modulators (amitriptyline, duloxetine) PainLidocaine management Morphine infusion gels Topical analgesia ¹Inpatients with calciphylaxis/hyperparathyroidism ²In patients withcalciphylaxis/hyperphosphatemia

Several of the compounds described as additional therapeutic agentschange the thermodynamics of the crystallization process by modifyingthe concentration of the ions present in the structure of thecalcium-containing crystal that results in an ectopic calcification.This sub-group includes calcimimetics, phosphate chelators, thiosulfate,or vitamin D.

Calcimimetics allow the calcium and phosphate concentration to becontrolled by regulating blood PTH levels. Said compounds include, e.g.,cinacalcet, NPS R-467, NPS R-568, and KAI-4169.

In some aspects, the combination composition comprises a vitaminselected from vitamin B, vitamin D, vitamin K or a combination thereof.Although with a different mechanism of action, vitamin D has a similareffect. The vitamin D is preferably selected from the group consistingof calciferol, ergocalciferol (Vitamin D2), cholecalciferol (VitaminD3), doxercalciferol, paricalcitol alfarol, alpha-calcidol calcidiol,calcitriol, derivatives or pharmaceutically acceptable salts thereof, orany combinations thereof.

Phosphate chelators act by sequestering phosphate thereby reducing thesystemic concentration thereof in blood. The phosphate binder cancontain a metal or be metal-free. Metal-free chelators include, e.g.,sevelamer. Metal-containing chelators include, e.g., various calcium,iron, lanthanum, aluminum and magnesium salts. Thiosulfate is a chelatorthat reduces the free calcium concentration in blood.

Other compounds (e.g., pyrophosphate, citrate, bisphosphonates,antihypertensives, anticholesteremic agents, vitamin B, or vitamin K)that can be used in combination therapies act against the alteredcalcium and phosphate metabolism kinetically by attempting to stop thecrystallization process or altering bone metabolism by increasing theamount of repressor factors (pyrophosphate, citrate, vitamin B, vitaminK, bisphosphonates) or by reducing the quantity of promoter factors(necrotic remains or organic matter in the case of antihypertensives orlipid deposits in the case of anticholesteremic agents).

In some aspects, the bisphosphonate can contain nitrogen or benitrogen-free. In some aspects, the bisphosphonate can be selected fromthe group consisting of etidronate, alendronate, risedronate,zoledronate, tiludronate, pamidronate, monidronate, neridronate,pamidronate, olpadronate, clodronate, ibandronate, and combinationsthereof.

In some aspects, the combination therapy can comprises ananticholesteremic agent selected from the group consisting of statins,fibrates, niacin, acid sequestrants, ezetimibe, lomitapide,phytosterols, orlistat, or combinations thereof.

Compounds that can be also used for the treatment of ectopiccalcifications also include those disclosed in U.S. Pat. No. 9,629,872,International Publ. No. WO2017131127, U.S. Pat. Nos. 5,362,886,4,024,175, and 3,159,581, all of which are herein incorporated byreference in their entireties.

VIII. Articles of Manufacture and Kits

The present disclosure also provides articles of manufacture and kits.Such articles of manufacture and kits can comprise a container (e.g., abox) comprising one or more vials containing a formulation comprisingone or more of the inositol phosphates of the present disclosure and/orsolvents for their administration according to the methods disclosedherein. A kit or article of manufacture provided according to thisdisclosure can also comprise brochures or instructions describing theprocess of administration and dosages disclosed herein. In some aspects,kit or article of manufacture can comprise multiple vials, each one ofthem containing a single dose. In other aspects, kit or article ofmanufacture can comprise one or more vials, each one of them comprisingmore than one dose.

In some aspects, the article of manufacture is a bag containing asolution of an inositol phosphate of the present disclosure. In otheraspects, the article of manufacture is a bottle (e.g., a glass bottle ora plastic bottle) containing a solution of an inositol phosphate of thepresent disclosure. In some aspects, the article of manufacture is a bagcontaining an inositol phosphate of the present disclosure in powderform for reconstitution in a appropriate solvent. In other aspects, thearticle of manufacture is a bottle (e.g., a glass bottle or a plasticbottle) containing an inositol phosphate of the present disclosure inpowder form for reconstitution in a appropriate solvent.

The kits and articles of manufacture can include instructions forcarrying out one or more administrations of the inositol phosphate ofthe present disclosure according to the methods and dosages disclosedherein.

Instructions included in the kits and articles of manufacture can beaffixed to packaging material or can be included as a package insert.While the instructions are typically written or printed materials theyare not limited to such. Any medium capable of storing such instructionsand communicating them to an end user is contemplated. Such mediainclude, but are not limited to, electronic storage media (e.g.,magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM),and the like. As used herein, the term “instructions” can include theaddress of an internet site that provides the instructions.

EXAMPLES Example 1

A Phase 2 Open-Label Single-Arm Study to Assess the Effect of SNF472 onWound Healing in Subjects with Calciphylaxis

Background

Calciphylaxis in end-stage renal disease is characterized by painfulnecrotic skin ulcers and high mortality. There are no approvedtherapies. SNF472, an intravenous formulation of myo-inositolhexaphosphate, selectively inhibits formation and growth ofhydroxyapatite crystals, the final common pathway in vascularcalcification. This phase 2 study evaluated SNF472 in the treatment ofcalciphylaxis.

Methods

In this open-label, single-arm study, subjects with calciphylaxis and onhemodialysis received intravenous SNF472 6-9 mg/kg during thrice weeklydialysis for 12 weeks, on top of standard care. The primary endpoint wasBates-Jensen Wound Assessment Tool (BWAT). Pain visual analog scale(VAS), wound quality of life (QoL), and qualitative wound image reviewwere secondary endpoints. Quantitative changes from baseline to week 12were analyzed for all subjects with multiple imputation; qualitativewound image review was analyzed descriptively for subjects who completed12 weeks of SNF472 treatment.

Results

Among the 14 subjects who were enrolled and received SNF472, significantimprovements from baseline to week 12 were observed for total BWAT score(mean, −8.1; P<0.001), pain VAS (mean, −23.6 mm; P=0.014), and Wound-QoLglobal score (mean, −0.9; P=0.003). Qualitative wound image reviewshowed improvement for 8 of 11 subjects who completed 12 weeks oftreatment. Adverse events and deaths (n=2) were consistent with ahemodialysis population. Eight subjects experienced serious adverseevents, none of which were considered related to SNF472.

Conclusions

The results of this phase 2 study indicate that SNF472 is tolerated welland calciphylaxis patients had benefits across multiple parameters,supporting a phase 3 study of SNF472 for calciphylaxis.

Materials and Methods (1) Study Design

This was an open-label, single-arm, repeat-dose phase 2 clinical studyat 11 study centers in the United States and England to investigate theeffect of SNF472 in patients with calciphylaxis. After screening,eligible subjects were enrolled and received SNF472 intravenously duringhemodialysis 3 times weekly for 12 weeks. A follow-up safety visit wasconducted 1 week after the last SNF472 dose. SNF472 was administered byslow infusion for 2.5 to 4 hours using the dialysis system. The dose ofSNF472 administered at each session was 400, 450, 700, or 900 mg, basedon the subject's dry body weight at screening (50 to <66 kg, 66 to <81kg, 81 to <111 kg, or 111 to 150 kg, respectively). SNF472 treatment wasadded to standard of care in accordance with the study center's standardprocedures.

(2) Subjects

Eligible subjects were men or women ≥18 years of age who were eithernewly diagnosed with calciphylaxis or had recurrent calciphylaxis thathad been dormant with no skin lesion involvement for at least 90 daysfrom study start (new or recurrent diagnosis was made within 5 weeks ofstudy start). Subjects were required to be receiving maintenancehemodialysis and have pain (at least minimal) on the pain VAS or theywere receiving analgesics stronger than nonsteroidal anti-inflammatorydrugs.

Key exclusion criteria were pregnancy, body weight above 150 kg, bodymass index >35 kg/m² and central (abdominal) ulcers, bisphosphonatetreatment within 12 months before entering into the study, severeillness with expected survival ≤6 months, and scheduledparathyroidectomy. Subjects signed written informed consent toparticipate. This study was conducted in accordance with the ethicalprinciples that originate from the Declaration of Helsinki and that areconsistent with International Council for Harmonisation Guidelines onGood Clinical Practice and regulatory requirements.

(3) Assessments

Investigators documented the severity of the primary lesion (the largestone) with the BWAT (Bates-Jensen & Sussman “Tools to measure woundhealing.” In: Wound Care: A collaborative practice manual for healthprofessionals. Edited by SUSSMAN, C., BATES-JENSEN, B., Philadelphia,Pa., Lippincott Williams & Wilkins, 2012, pp 131-161) at weeks 1, 2, 4,6, 8, 10, 12, and 13 (follow-up). The BWAT uses a scale of 1 (best) to 5(worst) for each of 13 items: size, depth, edges, undermining orpockets, necrotic tissue type, necrotic tissue amount, exudate type,exudate amount, surrounding skin color, peripheral tissue edema,peripheral tissue induration, granulation tissue, epithelialization. Thetotal BWAT score was the sum of these individual scores, with a possiblerange from 13 to 65. Two additional items (location and shape) were notscored.

At the same visits as the BWAT assessments, subjects recorded theintensity of wound pain, using a VAS from 0 (no pain) to 100 (worstpossible pain). At weeks 1, 6, and 12, subjects completed the Wound-QoLquestionnaire containing 17 questions about impairment of QoL that arecoded from 0 (not at all) to 4 (very much) (Augustin (2017), supra).

In addition to a global score, other items can be used to calculatesubscale scores for impairment of the body (items 1-5), psyche (items6-10), and everyday life (items 11-16).

Wound images were obtained for each subject at baseline and every 2weeks until week 12. Two reviewers reviewed each image and discussedindividual cases if there was discordance between their assessments. Inthe first step, baseline and week 12 images for each subject wererandomly labeled “A” and “B” to blind the reviewers. The blindedreviewers determined which was worse, or if both were the same. In thesecond step, the reviewers examined all images, without blinding, andrated the wound as worsened, improved, or no change from baseline toeach visit.

Safety assessments included treatment-emergent adverse events at anytime; ECG at weeks 1, 6, 12, and 13 (follow-up); and clinicallaboratories at screening, weeks 1, 6, 12, and 13 (follow-up). Bloodsampling for pharmacokinetics occurred at day 1 and week 12 day 5.

(4) Statistical Analysis

The primary efficacy endpoint was the absolute change in total BWATscore from baseline to week 12 for the primary lesion. Secondaryefficacy endpoints for wound healing were absolute change from baselinein BWAT total and component scores by visit and qualitative change frombaseline in wound images. Other secondary efficacy endpoints wereabsolute change from baseline by visit in the pain VAS score andabsolute change from baseline at weeks 6 and 12 in QoL global score andQoL subscale scores.

The primary analysis set for efficacy was the intention-to-treatpopulation, which included subjects who received at least one dose ofSNF472 and had at least one postbaseline efficacy measurement. Theprimary endpoint and quantitative secondary endpoints were analyzedusing paired Student's t-tests. Absolute change from baseline wasassessed with a multiple imputation method for missing data.

Sensitivity analyses of quantitative endpoints in the intention-to-treatpopulation used the last-observation-carried-forward method and noimputation (observed cases). Additional sensitivity analyses ofquantitative endpoints used the per-protocol population of subjects whoreceived at least 75% of SNF472 doses and did not violate the protocolin a way that might have affected the evaluation of the effect of thestudy drug. Absolute change in quantitative endpoints from baseline toweek 12 were also assessed for subgroups based on sodium thiosulfate useat baseline, using multiple imputation in the intention-to-treatpopulation. Imaging results were summarized using descriptivestatistics.

Analyses of pharmacokinetic data included all subjects who received atleast one dose of SNF472 and for whom the primary pharmacokineticparameter (postdose SNF472 concentration) could be determined.Descriptive statistics were presented by visit and time point.Accumulation from day 1 to week 12 was assessed by comparing thedifference in postdose concentrations between the visits. Accumulationwas declared if the 90% CI of the difference did not include the value0.

Safety analyses included all subjects who received at least one dose ofSNF472. Subject incidences of adverse events and serious adverse eventswere summarized descriptively. For each 12-lead ECG variable, theabsolute change from the predose to postdose measurement at each visitand the absolute change from baseline to all other predose measurementswere summarized descriptively.

Results (1) Subject Disposition

All 14 subjects who were enrolled in the study received at least onedose of SNF472 and were included in efficacy (intention-to-treat),safety, and pharmacokinetics analyses. Eleven (78.6%) subjects completedthe study and were included in per-protocol analyses (TABLE 2).

TABLE 2 Subject disposition (intention-to-treat population) All Subjects(n = 14) Completed study/per protocol 11 (79) Early discontinuation 3(21) Reasons for discontinuation: Subject withdrew consent 1 (7) Death 1(7) Withdrew from dialysis (led to death) 1 (7) Adverse event 0 Lost tofollow-up 0 Values are n (%).

Reasons for early study discontinuation were withdrawal of subjectconsent (n=1), death (n=1), and withdrawal from hemodialysis leading todeath (n=1).

(2) Baseline Characteristics

The mean (SD) age of study participants was 60.5 (14.1) years (range,34-90) (TABLE 3).

TABLE 3 Demographics and baseline characteristics SNF472 Parameter (n =14) Age, yr 60.5 ± 14.1 Range 34-90 Years on hemodialysis 3.8 ± 1.1Range 0.03-15   Sex, n (%) Female 11 (78.6) Race, n (%) White 10 (71.4)American Indian/Alaska Native, n (%) 2 (14.3) Black/African American, n(%) 2 (14.3) Weight, kg 85.9 ± 23.6 Body mass index, kg/m² 31.7 ± 8.4 Intense pain at baseline, n (%) 13 (92.9) Firm, calcified lesion, n (%)10 (71.4) Baseline concomitant medications Warfarin, n (%) 2 (14.3)^(a)Sodium thiosulfate, n (%) 11 (78.6)^(b) Data are mean ± SD unlessotherwise stated. ^(a)1 subject stopped warfarin at week 3 and the othersubject continued warfarin. ^(b)1 subject stopped sodium thiosulfate atweek 2 and other subjects continued sodium thiosulfate; 1 additionalsubject started sodium thiosulfate at week 7.

The mean (SD) duration of hemodialysis at baseline was 3.8 (1.1) years.Eleven (78.6%) subjects were female and 10 (71.4%) were white. Atbaseline, sodium thiosulfate was used by 11 (78.6%) subjects andwarfarin by 2 (14.3%). One subject each stopped sodium thiosulfate (week2) and warfarin (week 3) during the study; another subject startedsodium thiosulfate on study (week 7). Among the 11 subjects receivingsodium thiosulfate at baseline, the mean length of time on sodiumthiosulfate before the first dose of SNF472 was 19 days (range 2-30days). Ten (71.4%) subjects had firm, calcified subcutaneous tissuesurrounding the lesion at baseline. Thirteen (92.9%) subjects reportedintense pain at baseline; the subject without intense pain was receivingopioid medications.

(3) Total Bates-Jensen Wound Assessment Tool Score

For the primary endpoint of total Bates-Jensen Wound Assessment Tool(BWAT) score for the primary lesion among all subjects, mean (SD) scoresimproved from 33.6 (9.6) at baseline to 25.6 (7.3) at week 12 (FIG. 2A).SNF472 treatment was associated with statistically significantimprovement, with a mean (SD) change of −8.1 (8.5) from baseline to week12 (95% CI, −12.7 to −3.4; P<0.001; TABLE 4).

TABLE 4 Changes from baseline to week 12 for the primary and secondaryquantitative endpoints with SNF472 treatment (intention-to-treatpopulation with multiple imputation) Baseline Week 12 Change (n = 14) (n= 14) (n = 14) Total BWAT (primary) Mean (SD) 33.6 (9.6) 25.6 (7.3) −8.1(8.5) 95% CI −12.7, −3.4 P-value <0.001  Median (range) 34.0 (16, 46)26.0 (16, 38) −6.0 (−28, 1) Pain VAS (mm) (secondary) Mean (SD) 71.8(29.2) 48.1 (28.6) −23.6 (30.0) 95% CI −42.6, −4.7 P-value 0.015 Median(range) 81.0 (0, 100) 54.2 (0, 88) −11.0 (−80, 17) Wound-QoL globalscore (secondary) Mean (SD) 2.44 (0.89) 1.54 (0.90) −0.9 (0.87) 95% CI−1.49, −0.31 P-value 0.003 Median (range) 2.50 (0.6, 3.7) 1.63 (0.0,2.9) −0.79 (−2.5, 0.5) BWAT, Bates-Jensen Wound Assessment Tool; VAS,visual analog scale.Possible scores: total BWAT, 13 (best) to 65 (worst); pain VAS, 0 mm (nopain) to 100 mm (worst possible pain); Wound-QoL, 0 (no impairment) to 4(very much impairment).

Using only observed data, total BWAT score improved progressively, withstatistically significant improvements from baseline at weeks 10 and 12(FIG. 2B). Significant improvements from baseline to week 12 wereobserved in the BWAT component scores for peripheral tissue induration(mean change, −1.3; P=0.011), skin color surrounding wound (mean change,−1.2; P=0.034), granulation tissue (mean change, −1.2; P=0.024), andexudate amount (mean change, −1.0; P=0.026; FIG. 3). Sensitivityanalyses (TABLE 5) showed consistent improvements in BWAT from baselineto week 12 in the per-protocol population with multiple imputation(P=0.002), the intention-to-treat population with observed data(P=0.041), and the intent-to-treat population withlast-observation-carried-forward imputation (P=0.021).

(4) Pain

For the secondary endpoint of pain VAS for the primary lesion among allsubjects, mean (SD) scores improved from 71.8 (29.2) mm at baseline to48.1 (28.6) mm at week 12 (FIG. 4A). SNF472 treatment was associatedwith statistically significant improvement, with a mean (SD) change of−23.6 (30.0) mm from baseline to week 12 (95% CI, −42.6 to −4.7;P=0.015; TABLE 4). Using only observed data, pain VAS score improvedsignificantly from baseline to weeks 6, 8, and 12 (FIG. 4B).

Sensitivity analyses (TABLE 5) showed consistent improvements in painfrom baseline to week 12 for the per-protocol population with multipleimputation (P=0.017), the intention-to-treat population with observeddata (P=0.020), and the intent-to-treat population withlast-observation-carried-forward imputation (P=0.032).

TABLE 5 Sensitivity analyses: change from baseline to week 12 withSNF472 treatment ITT, LOCF ITT, Observed Cases Baseline Week 12 Change*Baseline Week 12 Change* Total (n = 14) (n = 14) (n = 14) (n = 12) (n =7) (n = 7) BWAT Mean 33.6 (9.6) 27.0 (9.0) −6.6 (9.5) 34.3 (9.6) 22.0(6.9) −8.0 (9.6) (SD) 95% −12.1, −1.2 −16.9, 0.9 CI P-value 0.021 0.071Median 34.0 (16, 46) 26.0 (16, 46) −5.5 (−28, 7) 34.0 (16, 46) 18.0 (16,34) −6.0 (−28, 1) (range) Pain (n = 14) (n = 14) (n = 14) (n = 14) (n =10) (n = 10) VAS Mean 71.8 (29.2) 51.8 (31.5) −20.0 (31.2) 71.8 (29.2)43.0 (31.1) −26.00 (35.1) (SD) 95% −38.0, −2.0 — — −51.1, −0.9 CIP-value 0.032 0.044 Median 81.0 (0, 100) 60.0 (0, 95) −8.5 (−80, 17)81.0 (0, 100) 47.5 (0, 85) −10.0 (−80, 17) (range) Wound- (n = 14) (n =14) (n = 14) (n = 14) (n = 14) (n = 14) QoL Global Mean 2.44 (0.89) 1.76(1.16) −0.68 (0.92) 2.44 (0.89) 1.29 (1.07) −1.05 (1.01) (SD) 95% −1.20,−0.15 −1.73, −0.37 CI P-value 0.016 0.006 Median 2.50 (0.6, 3.7) 1.68(0.0, 3.9) −0.50 (−2.5, 0.5) 2.50 (0.6, 3.7) 1.29 (0.0, 2.9) −0.94(−2.5, 0.5) (range) Per Protocol, Multiple Imputation Baseline Week 12Change* Total (n = 11) (n = 11) (n = 11) BWAT Mean 32.3 (10.5) 23.3(6.4) −8.9 (9.5) (SD) 95% −14.6, −3.3 CI P-value 0.002 Median 33.0 (16,46) 24.1 (16, 34) −6.0 (−28, 1) (range) Pain (n = 11) (n = 11) (n = 11)VAS Mean 69.1 (31.6) 43.8 (29.6) −25.3 (33.4) (SD) 95% −46.0, −4.5 CIP-value 0.017 Median 80.0 (0, 100) 52.2 (0, 85) −10.0 (−80, 17) (range)Wound- (n = 14) (n = 14) (n = 14) QoL Global Mean (SD) 2.44 (0.89) 1.54(0.90) −0.90 (0.87) 95% CI −1.49, −0.31 P-value 0.003 Median 2.50 (0.6,3.7) 1.63 (0.0, 2.9) −0.79 (−2.5, 0.5) (range) ITT, intention-to-treat;LOCF, last observation carried forward.

(5) Quality of Life

For the secondary endpoint of wound quality of life (Wound-QoL) globalscore, mean (SD) scores improved from 2.44 (0.89) at baseline to 1.54(0.90) at week 12 (FIG. 5). SNF472 treatment was associated with astatistically significant improvement in mean (SD) change of −0.9 (0.87)from baseline to week 12 (95% CI, −1.49 to −0.31; P=0.003; TABLE 5).Wound-QoL subscales also showed statistically significant mean (SD)improvements from baseline to week 12: body, −0.86 (0.87), P=0.004; andpsyche, −1.33 (1.14), P<0.001 (FIG. 5). Improvement in everyday life(mean, −0.65; SD, 0.99) approached statistical significance (P=0.051;FIG. 5).

Sensitivity analyses (TABLE 5) showed consistent improvements inWound-QoL global score from baseline to week 12 for the per-protocolpopulation with multiple imputation (P=0.016), the intention-to-treatpopulation with observed data (P=0.006), and the intent-to-treatpopulation with last-observation-carried-forward imputation (P=0.003).

(6) Subgroup Analyses by Sodium Thiosulfate Use

Only 2 subjects received SNF472 without sodium thiosulfate, limitinginterpretation of the subgroup analyses. However, mean improvements frombaseline to week 12 in BWAT and pain VAS were observed in the subjectswho received SNF472 without concomitant sodium thiosulfate, includingstatistically significant improvement for total BWAT score (P=0.003).

(7) Qualitative Wound Assessments

In the unblinded review in which the reviewers knew which visit wasassociated with each image, they reported that the primary lesionimproved qualitatively for 8 of 11 subjects at week 12; many subjectsdemonstrated qualitative improvement by week 6 of SNF472 treatment (FIG.6). Representative images for qualitative wound healing assessments atbaseline and week 12 are provided in FIG. 7, including 2 examples ofwound healing and 1 example of worsening.

(8) Pharmacokinetics

The median (range) postdose plasma SNF472 concentration was 15,845(1830-411,197) ng/mL at day 1 and 13,679 (2808, 40,192) ng/mL at week 12day 5. The mean change in postdose SNF472 concentration from day 1 toweek 12 day 5 was −2522 ng/mL, indicating that SNF472 did not accumulatewith repeated dosing. Plasma SNF472 concentration was in the expectedrange in all subjects except 1 subject in whom SNF472 was below thelimit of quantitation postdose at week 12. The wound also worsened inthis subject, as shown in FIG. 7.

(9) Safety

At least one treatment-emergent adverse event was reported for 13(92.9%) subjects (TABLE 6).

TABLE 6 Summary of treatment-emergent adverse events (safety analysisset) SNF472 (n = 14) Category n (%) Any adverse event 13 (92.9) Adverseevents possibly related to SNF472 4 (28.6) Adverse events leading todrug discontinuation 2 (14.3) Worst severity of adverse events Grade 3 5(35.7) Grade 4 0 Grade 5 (fatal) 2 (14.3)^(a) Any serious adverse event7 (50.0)^(a) Adverse events reported for >1 subject Arteriovenousfistular thrombosis 2 (14.3) Cellulitis 2 (14.3) Diarrhea 2 (14.3) ECGQT interval prolonged 2 (14.3) Fluid overload 2 (14.3) Hypertension 2(14.3) Hypoesthesia 2 (14.3) Nausea 2 (14.3) Skin lesion 2 (14.3) ECG,electrocardiogram. ^(a)Neither of the deaths and none of the otherserious adverse events were considered by the investigator to be relatedto SNF472 treatment.

Adverse events reported for more than one subject were arteriovenousfistula thrombosis, cellulitis, diarrhea, fluid overload, hypertension,hypoesthesia, nausea, prolonged QT interval, and skin lesion (2 [14.3%]subjects each). Most adverse events were mild or moderate in severity.Five (35.7%) subjects had grade 3 (severe) adverse events and no subjecthad grade 4 (life-threatening) adverse events. Two (14.3%) subjects hadgrade 5 (fatal) adverse events (cardiorespiratory arrest and cardiogenicshock). The event of cardiorespiratory arrest occurred subsequent towithdrawal from hemodialysis. Aside from these 2 subjects, no subjectdiscontinued study treatment for an adverse event. Seven (50.0%)subjects had serious adverse events. Infections and infestations was themost common System Organ Class of serious adverse events (includingcellulitis, gangrene, infection, sepsis, and urinary tract infection in1 subject each). Other serious adverse events were abdominal wounddehiscence, cardiogenic shock, cardiorespiratory arrest, dry gangrene,fluid overload, hematemesis, hypertensive emergency, and pulmonary edemain 1 subject each. No serious adverse event was considered by theinvestigator to be related to SNF472 treatment.

No clinically relevant trends in ECG intervals were observed, eitherfrom predose to postdose, or between predose assessments on day 1, week6 day 1, and week 12 day 5. The majority of subjects with assessmentshad ECG abnormalities that were not clinically significant, eitherpredose or postdose at several assessments. Three subjects had ECGabnormalities that were reported as adverse events: prolonged QTinterval (2 subjects) and tachycardia (1 subject). One prolonged QTinterval adverse event was considered by the investigator unlikely to berelated to SNF472 treatment; it occurred at the follow-up visit 21 daysafter the last dose of SNF472. The other ECG adverse events wereconsidered possibly related. Each ECG abnormality adverse event was mildto moderate in severity, was asymptomatic, and resolved withouttreatment.

Discussion

This was the first multicenter, international, prospective,interventional study of a treatment for calciphylaxis. Statisticallysignificant improvement in wound healing for the primary lesion wasobserved with SNF472 treatment. Statistically significant improvement inpain and Wound-QoL scores also were observed with SNF472 treatment.There was no observed accumulation of SNF472 over time with repeateddosing. SNF472 was generally well tolerated; serious adverse events wereconsistent with the study population. These results support conducting aphase 3 study of SNF472 for CUA.

It is to be appreciated that the Detailed Description section, and notthe Summary and Abstract sections, is intended to be used to interpretthe claims. The Summary and Abstract sections may set forth one or morebut not all exemplary embodiments of the present invention ascontemplated by the inventor(s), and thus, are not intended to limit thepresent invention and the appended claims in any way.

The present invention has been described above with the aid offunctional building blocks illustrating the implementation of specifiedfunctions and relationships thereof. The boundaries of these functionalbuilding blocks have been arbitrarily defined herein for the convenienceof the description. Alternate boundaries can be defined so long as thespecified functions and relationships thereof are appropriatelyperformed.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingknowledge within the skill of the art, readily modify and/or adapt forvarious applications such specific embodiments, without undueexperimentation, without departing from the general concept of thepresent invention. Therefore, such adaptations and modifications areintended to be within the meaning and range of equivalents of thedisclosed embodiments, based on the teaching and guidance presentedherein. It is to be understood that the phraseology or terminologyherein is for the purpose of description and not of limitation, suchthat the terminology or phraseology of the present specification is tobe interpreted by the skilled artisan in light of the teachings andguidance.

The breadth and scope of the present invention should not be limited byany of the above-described exemplary embodiments but should be definedonly in accordance with the following claims and their equivalents.

The claims in the instant application are different than those of theparent application or other related applications. The Applicanttherefore rescinds any disclaimer of claim scope made in the parentapplication or any predecessor application in relation to the instantapplication. The Examiner is therefore advised that any such previousdisclaimer and the cited references that it was made to avoid, may needto be revisited. Further, the Examiner is also reminded that anydisclaimer made in the instant application should not be read into oragainst the parent application.

What is claimed is:
 1. A method to treat or prevent ectopiccalcification and/or the consequences thereof in a subject in needthereof comprising administering a dose of an inositol phosphate or ananalog or derivative thereof in a dosage of about 6 mg to 9 mg per kgper day to the subject, wherein the administration of the dosageeffectively treats or prevents ectopic calcification and/or theconsequences thereof in the subject.
 2. The method of claim 1, whereinthe inositol phosphate comprises a compound of formula I, apharmaceutically acceptable salt thereof, or a combination thereof:

wherein R₁, R₃, R₅, R₇, R₉ and R₁₁ independently represent OH, acompound of formula II, or a compound of formula III, or a compound forformula IV:

(ii) R₂, R₄, R₆, R₈, R₁₀, R₁₂ and R₁₃ represent H; (iii) at least one ofR₁, R₃, R₅, R₇, R₉ and R₁₁ represents a compound of formula II, formulaIII or formula IV, and (iv) zero, one, or two of R₁, R₃, R₅, R₇, R₉ andR₁₁ represent a heterologous moiety.
 3. The method of any one of claim 1or 2, wherein the inositol phosphate contains between 1 and 6 phosphategroups.
 4. The method of claim 3, wherein the inositol phosphate isinositol hexaphosphate.
 5. The method of claim 4, wherein the inositolhexaphosphate is myo-inositol hexaphosphate.
 6. The method of any one ofclaims 1 to 5, wherein the dosage is of about 7 mg per kg per day to thesubject.
 7. The method of any one of claims 2 to 6, wherein theheterologous moiety comprises a half-life extending moiety.
 8. Themethod of claim 7, wherein the heterologous moiety comprises apolyethylene glycol or a polyglycerol.
 9. The method of any one ofclaims 1 to 8, wherein the concentration of inositol phosphate or ananalog or derivative thereof in each dose is between about 10,000 μg/mLand about 100,000 μg/mL.
 10. The method of any one of claims 1 to 8,wherein the concentration of inositol phosphate or an analog orderivative thereof in each dose is between about 12.5 mM and about 135mM.
 11. The method of any one of claims 1 to 10, wherein the dosage isadministered as a single daily dose.
 12. The method of any one of claims1 to 10, wherein the dosage is administered as multiple daily doses. 13.The method of any one of claims 1 to 12, wherein the dosage isadministered at least once a week.
 14. The method of any one of claims 1to 13, wherein the dosage is administered 2, 3, 4, 5, 6 or 7 times perweek.
 15. The method of any one of claims 1 to 14, wherein the dosage isadministered for at least one week.
 16. The method of any one of claims1 to 15, wherein the dosage is administered for about 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31 or 32 weeks.
 17. The method of any one of claims1 to 16, wherein the dosage is administered for at least 12 weeks. 18.The method of any one of claims 1 to 17, wherein the dosage isadministered for at least 24 weeks.
 19. The method of any one of claims1 to 18, wherein the administration of the dosage to the subjectinhibits the formation and/or growth of hydroxyapatite crystals.
 20. Themethod of any one of claims 1 to 19, wherein the ectopic calcificationis calciphylaxis calcification, metastatic calcification, dystrophiccalcification, iatrogenic calcification, idiopathic calcification, orsubcutaneous ectopic ossification.
 21. The method of any one of claims 1to 20, wherein the consequence of the ectopic calcification is afunctional complication, pain, a trophic complication, an infection, ora combination thereof.
 22. The method of claim 21, wherein the functioncomplication is a limitation of range of motion and/or joint function.23. The method of claim 21, wherein the trophic complication is ischemiaand/or a lesion.
 24. The method of claim 23, wherein the lesion isnecrosis of the cutaneous and/or subcutaneous tissues.
 25. The method ofany one of claims 1 to 24, wherein administration of the dosage to thesubject causes a reduction in lesions as determined by the Bates-JensenWound Assessment tool.
 26. The method of claim 25, wherein the reductionin lesions comprises a reduction in the severity of the lesions, areduction in the size of the lesions, and reduction in the duration ofthe lesions, or a combination thereof.
 27. The method of any one ofclaims 1 to 26, wherein administration of the dosage to the subjectcauses an improvement in lesion healing.
 28. The method of any one ofclaims 1 to 27, wherein administration of the dosage to the subjectcauses a reduction in pain.
 29. The method of any one of claims 1 to 28,wherein administration of the dosage to the subject causes animprovement on global wound quality of life (QoL) as determined by usinga validated wound-associated QoL questionnaire.
 30. The method of anyone of claims 1 to 29, wherein the subject has end-stage renal disease.31. The method of any one of claims 1 to 30, wherein the subject is onhemodialysis.
 32. The method of any one of claims 1 to 31, wherein thesubject is human.
 33. The method of any one of claims 1 to 32, whereinthe administration is parenteral.
 34. The method of claim 33, whereinthe parenteral administration is intravenous.
 35. The method of claim34, wherein the intravenous administration is by bolus injection or byinfusion.
 36. The method of any one of claims 1 to 32, wherein theadministration is topical.
 37. A method to treat or preventcalciphylaxis calcification and/or the consequences thereof in a subjectin need thereof comprising administering an intravenous dose ofmyo-inositol hexaphosphate or an analog or derivative thereof, in adosage of about 6 mg to 9 mg per kg per day to the subject, administered3 times a week for 12 weeks, wherein the administration of the dosageeffectively treats or prevents calciphylaxis calcification and/or theconsequences thereof in the subject.
 38. An intravenous dose ofmyo-inositol hexaphosphate in a dosage of about 6 mg to 9 mg per kg perday to the subject, administered 3 times a week for 12 weeks as taken bya patient in a therapeutically effective amount sufficient to treat orprevent calciphylaxis calcification and/or the consequences thereof in asubject.
 39. A kit or article of manufacture comprising at least onecontainer comprising an parenteral or topical dose of inositolhexaphosphate or an analog or derivative thereof and instructions foradministration according to the method of any one of claims 1 to 37.